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PL 17901/0246-7

UKPAR AstraZeneca UK Ltd, Pulmicort CFC-free Inhalers 100 and 200 micrograms

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Pulmicort® CFC-free Inhaler 100 micrograms Pulmicort® CFC-free Inhaler 200 micrograms

Budesonide

PL 17901/0246-7 AstraZeneca UK Ltd

UKPAR Table of Contents

Page Lay Summary 2 Scientific Discussion 3 Overall Conclusion And Risk Benefit/Analysis 66 Steps Taken During Assessment 67 Steps Taken After Assessment 68 Summary of Product Characteristics 69 Patient Information Leaflet 92 Labelling 94

PL 17901/0246-7

Pulmicort® CFC-free Inhaler (budesonide)

PL 17907/0246-7

Introductory Note to Reader This Public Assessment Report produced by the MHRA is written in the form of a date or time-based commentary on the assessment of the applications for Marketing Authorisations made by the Applicant. The document must therefore be read in its entirety in order to gain a complete and accurate understanding and awareness of the applications made, the assessment procedure and outcomes, the resolutions of any issues and the conclusions reached.

Lay Summary The MHRA granted Marketing Authorisations to AstraZeneca UK Ltd for Pulmicort® CFC-free Inhaler 100 and 200 micrograms on 24th September 2008 (PL 17901/0246-7). Budesonide (INN) is a well-known non-halogenated glucocorticosteroid that is used for inhalation treatment of asthma and rhinitis. The replacement of CFC- containing products is in order to reduce potential damage to the protective ozone layer by CFCs. The Applicant demonstrated that Pulmicort® CFC-free Inhaler is non-inferior to the Pulmicort® CFC Inhaler. The SPC, PIL and labelling was considered satisfactory. The quality of the product was found to be acceptable. It was concluded that the risk-benefit analysis for the product was considered to be positive hence, the Marketing Authorisations have been granted.


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Pulmicort® CFC-free Inhalers (budesonide) PL 17901/0246-7

Scientific Discussion

Table of Contents Page Introduction 4 Pharmaceutical assessment 4 Pre-clinical assessment 7 Medical assessment 8 Committee on Safety of Medicines recommendations and assessments of applicant responses 38


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INTRODUCTION Note: This assessment report has been updated to incorporate information provided by the Applicant in response to queries raised by the assessor and/or the Commission on Human Medicines during the assessment process. Updates are generally not included at the point where queries are raised but in later appropriate sections. Please therefore read the entire document in order to obtain full information. Please note however that all queries raised by the assessors and the Commission on Human Medicines were answered satisfactorily by the Applicant, as presented in the section “Committee on Safety of Medicines recommendations and assessments of applicant responses”. Based on a review of the data on quality, safety and efficacy the UK MHRA granted marketing authorisations for the medicinal products Pulmicort CFC-free Inhaler 100 micrograms (PL 17901/0247) and Pulmicort CFC-free Inhaler 200 micrograms (PL 17901/0246) on 24/09/2008. These are national applications for Pulmicort Inhaler 100 and 200 micrograms in accordance with Directive 2001/83/EC, Article 8.3 for a known active substance budesonide. These are line extensions for a change in the propellant (switch from chlorofluorocarbon (CFC) to hydrofluoroalkane (HFA)) to the applicant’s Pulmicort CFC Inhaler. Budesonide (INN) is a well-known non-halogenated glucocorticosteroid that is used for inhalation treatment of asthma and rhinitis. Since its first approval in 1981, budesonide has been marketed by AstraZeneca in different dosage forms for inhalation, one of which is a pressurised metered dose inhaler (pMDI) with a chlorofluorocarbon (CFC) propellant. The use of CFC propellants in medical inhalers is being phased out because of their implication in the depletion of the ozone layer. Therefore the objective of the present development is the provision of a non-CFC pMDI comparable in safety and efficacy to the existing AstraZeneca product and capable of replacing this in the market. PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE An appropriate specification based on the European Pharmacopoeia has been provided. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Budesonide is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory.


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Batch analysis data are provided and comply with the proposed specification. Satisfactory certificates of analysis have been provided for working standards used by the active substance manufacturer and finished product manufacturer during validation studies. Appropriate stability data have been generated supporting a retest period of 36 months, with no specific storage instructions. DRUG PRODUCT Other Ingredients The other ingredients of the drug product are Norflurane (HFA 134a) - a CFC-free propellant and magnesium stearate. Magnesium stearate conforms to the European Pharmacopoeia. Batch analysis data for batches of Norflurane have been provided and is acceptable. There are no excipients of human or animal origin and there are no novel excipients used in the manufacture of the drug product. Effect of orientation on delivered dose. The effect of resting time and re-priming on the product was also studied. An effect of storage orientation on delivered dose was noted and is discussed further on page 39. Impurity profiles Impurity profiles for both strengths of drug product were found to be similar to those for the reference products. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on batches of each strength. The results are satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System The product is contained in a pressurized aluminium container. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 2 years has been set, with the following storage conditions. Do not pierce or burn container even when empty Do not store above 30ºC Avoid flame and heat


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Keep in a specified position

ASSESSOR’S OVERALL CONCLUSIONS ON QUALITY AND ADVICE Further to the initial assessment there were two major issues raised that required resolution prior to the granting of Market Authorisations. . 1 The issue with the effect of orientation dependency on delivered dose is

considered to be major/critical as it would be very difficult to ensure patient compliance in this respect.

2 The dose uniformity test method which is not in line with the Ph. Eur.

Requirements is also considered a major point as all subsequent batch data and stability data have been generated with this test. There seems to be some intrinsic issue with dose uniformity as seen by some out of specification dose uniformity points observed in the stability data.

Further evidence was provided by the company that resolved these issues as described below.


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PRE-CLINICAL ASSESSMENT


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MEDICAL ASSESSMENT (October 2006)

1. INTRODUCTION Budesonide is a glucocorticosteroid that possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids. The two products for which Marketing Authorisations are being sought currently contain the same active ingredient, budesonide, as the previously authorised products. However, the original pressurised inhalation suspension products were formulated in an excipient mix including chlorofluorocarbon (CFC) products which are being phased out due to evidence implicating them in the depletion of the ozone layer. The two products are formulated in an excipient mix including the hydrofluoroalkane (HFA) propellant HFA-134a, a non-CFC alternative propellant.

Under the terms of the Montreal Protocol (1987) parties to the agreement agreed to phase out the use of CFCs including use in medicinal products due to concern over the contribution of CFCs to the depletion of the ozone layer. Initially the phase out of such use was to have taken place by the end of 1999; then the target for phase out was the end of 2006. AstraZeneca plc is a member of the International Pharmaceutical Aerosol Consortium for Toxicology Testing of the non-CFC propellant, HFA-134a (IPACT-I), a consortium of major pharmaceutical companies who manufacture pressurised metered dose inhalers (pMDIs) primarily for use in the management of asthma and chronic obstructive pulmonary diseases. In November 1993 IPACT-I applied to the then CPMP (now CHMP) for approval for the use of this non-CFC propellant, HFA-134a (1,1,1,2-tetrafluoroethane, Norflurane) as an alternative propellant in pressurised meter dose inhalers. 2. CLINICAL PHARMACOLOGY Budesonide formulated in an excipient mix including CFC propellants and administered via a pMDI has been authorised and available for use in the treatment of asthma since October 1981 and is approved in more than 70 countries worldwide. Clinical trials with budesonide (in all formulations) have involved over 61,000 patients and healthy volunteers, and post-marketing experience includes more than 11 billion patient treatment days. The clinical pharmacology of budesonide has been investigated previously and is the subject of many publications; the effects seen in human subjects are well known and are consistent with the effects of inhaled glucocorticoids. Therefore no new data have been provided in respect of the clinical pharmacology of budesonide in these applications other than studies to demonstrate that the pharmacokinetic and pharmacodynamic profiles of budesonide HFA pMDI are similar to those of budesonide CFC pMDI. In this regard two studies have been presented, both in healthy volunteers, one comparing single doses of the two formulations (CFC-free compared with CFC-containing formulations) and the other a 4-week comparative study to assess systemic safety. The requirement to phase out CFC-containing pMDIs has formed the basis for the development programme, planned to support a switch from budesonide CFC pMDI to


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budesonide HFA pMDI such that the current labelling for budesonide CFC pMDI would be applicable to budesonide HFA pMDI, and budesonide HFA pMDI would be shown to be pharmacokinetically equivalent and clinically non-inferior to budesonide CFC pMDI, and with a similar safety profile. Synopses of the two clinical pharmacology studies are presented in Appendix 5-4

2.1 Pharmacokinetics

Study No: SKYE 2021-01

A pharmacokinetic comparison of orally inhaled budesonide delivered via SkyePharma HFA metered dose inhaler and marketed CFC metered dose inhaler (Pulmicort, AstraZeneca) in healthy male and female volunteers. (n=40) The primary objective of this study was to compare the single dose pharmacokinetics of budesonide in two different formulations, one formulated in an excipient mix including CFC propellants and the other in an excipient mix including the non-CFC propellant, HFA-134a, at three dose levels when administered to healthy volunteers. The secondary objective was to evaluate the dose proportionality and relative bioavailability of the two strengths of budesonide formulated with propellant HFA-134a and to compare these with the reference CFC-containing product. The study was a single centre, randomised, open-label, four-way crossover, single dose study and saw recruitment of 40 male and female volunteers, aged 18 to 45 years. Each subject received two of three doses of budesonide (400, 800 or 1600µg) formulated with propellant HFA-134a (budesonide HFA pMDI) and the same two of the three doses of budesonide formulated with CFC propellants (budesonide CFC pMDI), i.e., each subject received a single dose of budesonide on four occasions and each occasion of dosing was followed by a wash-out period of at least two and not more than 7 days, between the four treatments. Plasma samples were collected for budesonide levels at pre-dose and at 10, 20, 30, 40, 60 and 90 minutes and 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post-dosing and for plasma cortisol levels at pre-dose and at 30 and 60 minutes and 2, 3, 4, 6, 8, 10 and 12 hours post-dosing and again at the follow-up examination. Adverse events were monitored at every visit, pre- and post-dosing, and at the follow-up examination, vital signs were measured at screening, pre-dose, and at 30 minutes and 12 hours post-dosing and at the follow-up examination, laboratory monitoring was performed at screening and at follow-up, and spirometry was carried out at screening, in the afternoon on the days immediately prior to dosing and at the follow-up examination.

Pharmacokinetic parameters included maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve from zero time to the specified time (12 hours) and from zero time to infinity (AUC0-t and AUC0-inf), median time to Cmax (tmax) and terminal phase half-life (t½). The pharmacodynamic parameter calculated for plasma cortisol was the AUC0-12. The primary statistical analysis was carried out in respect of AUC and Cmax for budesonide. Primary variables were dose normalised, logarithmically transformed and then subjected to Analysis of Variance (ANOVA) taking into account the factors treatment, period, sequence, dose and subject within sequence. Ninety percent confidence intervals (CI) of the ratio reference/test was calculated for both primary parameters and bioequivalence of the test and


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reference products concluded if the 90% CI for the ratios both fell within the pre-specified interval of 0.70-1.43. Tabular summaries of the pharmacokinetic and pharmacodynamic findings are presented in the study synopsis, Appendix 5-4, pages 7 and 8 of Appendix 5-4. Generally slightly higher systemic levels of budesonide were seen following budesonide HFA pMDI but the Applicant concludes that as the 90% CIs for the ratios of both AUC and Cmax fell within the pre-defined limits (and even within the tighter limits of 0.80-1.25) the two formulations could be said to be bioequivalent. Dose proportionality was apparent for both formulations over the dosing range (400-1600µg). For plasma cortisol levels the estimated ratios, test/reference (budesonide 100 HFA pMDI versus budesonide 200 CFC pMDI and budesonide 200 HFA pMDI versus budesonide 200 CFC pMDI) were close to unity, 1.02 (0.95, 1.09) and 0.95 (0.88, 1.04), respectively. However, when the arithmetic means and the geometric means are reviewed plasma cortisol levels would appear to be lower following budesonide 200 HFA pMDI administered in a dose of 1600µg than following budesonide 200 CFC pMDI administered in a dose of 1600µg.

Thirty two adverse events were reported by 19 subjects and the most common adverse event was headache. The majority of adverse events were described as mild and disappeared spontaneously without treatment. The Applicant concludes that a single oral inhalation of budesonide HFA pMDI or budesonide CFC pMDI over a dose range of 400µg to 1600µg was well tolerated and safe in healthy male and female volunteers.

2.2 Pharmacodynamics

Study No: SKY2021-004. A randomised, open-label active-controlled, parallel group, single centre, 4-week study to evaluate the safety of high dose budesonide after multiple dosing with investigational HFA metered dose inhaler and conventional CFC metered dose inhaler (Pulmicort) in healthy subjects. (n=48).

The primary objective of this study was to investigate the effect on the hypothalamic pituitary adrenocortical (HPA) axis of high dose budesonide (1600µg/day) administered as budesonide


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HFA pMDI and compared with budesonide CFC pMDI over a 4-week treatment period in healthy volunteers. The secondary objectives were to determine the local effects seen when switching from budesonide CFC pMDI to budesonide HFA pMDI and to compare the general safety of budesonide HFA pMDI with that of budesonide CFC pMDI. This study was a single centre, randomised, open-label, active-controlled, parallel group study and saw recruitment of 48 male and female volunteers (24 to each treatment group), aged 18 to 45 years. The primary safety outcome variable was the urinary cortisol/creatinine ratio (UCC) following collection of the 12-hour overnight urine at screening (pre-run-in), at the end of the run-in period/pre-treatment period/baseline visit (equals run-in day 7) and overnight on days 1 and 28 of the treatment period, to assess the suppressive effects of high dose budesonide on HPA axis function. Secondary variables included assessment of clinical symptoms such as cough, stridor and dysphonia and the incidence of treatment-emergent adverse events and changes in vital signs during the 4-week treatment period. Adverse events were monitored at every clinic visit and at the follow-up visit, vital signs were recorded at the screening visit, at the pre-run-in baseline visit, on treatment days 1, 8, 15, 22 and 29 and at the follow-up visit and laboratory monitoring was carried out at the screening visit, at the pre-run-in baseline visit and at the follow-up visit.

All subjects underwent a run-in period of 7 days during which they received budesonide CFC pMDI in a total daily dose of 1600 µg (800µg twice daily). On run-in day 7 subjects were randomised to one of the two treatment groups. Subjects attended the clinic at the end of each week of the treatment period. Following treatment with budesonide CFC pMDI (1600µg) during the run-in period the mean UCC decreased from 4.67 nmol/mmol to 3.52 nmol/mmol. No change was seen in mean UCC following the switch from budesonide CFC pMDI to budesonide HFA pMDI following one day of treatment; however, following 28 days of treatment with budesonide HFA pMDI mean UCC decreased from 3.38 nmol/mmol to 1.18 nmol/mmol. In the treatment group receiving budesonide CFC pMDI mean UCC showed an increase from 3.31 nmol/mmol following one day of treatment to 4.47nmol/mmol following 28 days of treatment. These data were recalculated subsequently excluding one subject in whom data showed extreme variability and the exclusion of this subject resulted in a fall in mean UCC from 3.39 nmol/mmol on treatment day 1 to 2.48 nmol/mmol on treatment day 28. Using log-transformed data there were no statistically significant differences seen between the treatment groups with respect to UCC on treatment day 1; however, the difference in UCC between the two treatments did become statistically significant on treatment day 28, estimated ratio of test to reference of 0.69, 90% CI 0.49, 0.98. The exclusion of the one subject with high variability in UCC data reduced the difference in mean UCC between the two treatment groups to a non-statistically significant difference with an estimated ratio of test to reference of 0.74, 90% CI 0.52, 1.05.

The number of subjects in whom the 12-hour overnight urinary cortisol value fell below the limit of quantification was comparable between the two treatment groups, budesonide HFA pMDI and budesonide CFC pMDI, 5 versus 6 subjects respectively at the end of the run-in period and 6 versus 8 subjects respectively at the end of the 28-day period. However, it should be noted that although it can be argued that more subjects recorded 12-hour overnight urinary cortisol values below the limit of quantification in the budesonide CFC pMDI treatment group, numerically lower UCC levels were seen in the budesonide HFA pMDI treatment group compared with the budesonide CFC pMDI treatment group.


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Twenty one subjects (44%) reported 49 adverse events during the run-in period; during the treatment periods 14 subjects (58%) receiving budesonide HFA pMDI reported 37 adverse events and 18 subjects (75%) receiving budesonide CFC pMDI reported 78 adverse events. Headache and pharyngolaryngeal pain were the most frequently reported adverse events, headache more frequently reported following budesonide CFC pMDI than budesonide HFA pMDI, 50% compared with 33% respectively; pharyngolaryngeal pain was reported equally in each treatment group (by 7 subjects, 29%). The majority of adverse events were mild in severity and there were no serious events reported. There were no deaths and no adverse events that led to treatment discontinuation. It was deemed by the investigator that the majority of adverse events were related to study treatments. Local side effects and all symptoms coded under respiratory, thoracic and mediastinal disorders were reported by fewer subjects receiving budesonide HFA pMDI than by subjects receiving budesonide CFC pMDI, 9 subjects (38%) and 13 subjects (54%), respectively. No increased incidence of local adverse events was seen following switching from the CFC-containing product to the CFC-free product and there were no clinically relevant findings observed in other parameters measured (laboratory data, vital signs, ECGs).

2.3 Clinical Assessor’s comment (March 2006) Please check this date is correct, as heading on page 8 says October 2006

No new data have been provided in respect of the clinical pharmacology of budesonide other than studies to demonstrate that the pharmacokinetic and pharmacodynamic profiles of budesonide HFA pMDI are similar to those of budesonide CFC pMDI and in this regard two studies have been presented in healthy volunteers. The clinical pharmacology of budesonide has been investigated previously and the effects seen in human subjects are well known and are consistent with the effects of inhaled glucocorticoids. The first of the two studies compared the single dose pharmacokinetics of budesonide in the two formulations and evaluated dose proportionality. Although generally slightly higher systemic levels of budesonide were seen following budesonide formulated with propellant HFA-134a the 90% confidence intervals for the ratios of both AUC and Cmax fell within the pre-defined limits and therefore the two formulations can be deemed to be bioequivalent. Dose proportionality was apparent for both formulations over the dosing range of 400-1600µg. This first study and the second study presented assessed systemic safety through the effects of budesonide on the HPA axis. The Applicant chose to assess the systemic effect on the HPA axis through the measurement of plasma cortisol in the first study and through 12-hour overnight urine collections and the measurement of the urinary cortisol/creatinine ratio in the second study. The 12-hour overnight urine is accepted as a measure of HPA axis function although it should be noted that current recommendations in respect of the measurement of systemic effects would request that the 24-hour urine collection be used rather than the 12-hour overnight collection. In both of these studies in healthy volunteers there is a suggestion of a slightly enhanced systemic effect with budesonide formulated with propellant HFA-134a (budesonide HFA pMDI) with lower plasma cortisol levels seen following the administration of 1600µg in the first study and a greater fall in urinary cortisol/creatinine ratio over four weeks treatment with a dose of 800µg twice daily in the second study. In this study this difference between the two formulations was statistically significant when all data were included in the analysis; however, the removal of one subject from the budesonide CFC pMDI treatment group in whom data collected were described as extremely variable, did reduce this statistically significant difference between treatments to a non-statistically significant difference. Numerically lower UCC levels were seen in the budesonide HFA pMDI treatment group compared with the budesonide CFC pMDI treatment group. Further data on this issue were supplied by the applicant and are discussed on page 41.


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3. CLINICAL EFFICACY 3.1 Overview

In December 1993 the CPMP published a Note for Guidance: Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products III/5378/93 – Final. Following the assessment of the submission from IPACT-I in which approval for the use of propellant HFA-134a in the clinical development of active drugs formulated in an excipient mix including HFA-134a as a propellant was gained, it was recommended that such clinical development should take full account of this Note for Guidance. The clinical programme submitted with these applications has been designed to demonstrate non-inferiority of budesonide HFA pMDI when compared with budesonide CFC pMDI in both adults and children with asthma through two separate pivotal clinical studies set up in parallel. The two studies compared the safety and efficacy of budesonide in two formulations, one in which budesonide is formulated with the non-CFC propellant, HFA-134a and the other in which budesonide is formulated with CFC propellants, at two dose levels, 400 and 800µg per day in adults and 400µg per day in children, over a treatment period of 12 weeks. A tabular overview of the clinical programme, including the two pivotal efficacy studies and the two clinical pharmacology studies is presented in Appendix 5-5 and synopses of the pivotal efficacy and safety studies are presented in Appendix 5-6.

3.2 Pivotal efficacy studies

Study No: SKY2021-002 A randomised, double-blind, active-controlled, parallel group, stratified, multicentre, 12-week study to evaluate the safety and efficacy after multiple dosing of investigational budesonide HFA metered dose inhalers compared with conventional budesonide CFC metered dose inhalers (Pulmicort) in patients with asthma. (n=322) Study No: SKY2021-003 A randomised, double-blind, parallel group, stratified, multicentre, 12-week safety and efficacy study of an investigational budesonide HFA metered dose inhaler and a conventional budesonide CFC metered dose inhaler (Pulmicort) in paediatric patients with asthma. (n=159) These studies will be described together initially as they both share a very similar study design, the major difference between the two studies being the population of patients studied. Study SKY2021-002 sees recruitment of adult patients with asthma aged 12 years and over, Study SKY2021-003 sees recruitment of children with asthma aged between 6 and 12 years. Both studies were multinational, multicentre studies carried out in 49 and 38 study sites, respectively, in Europe – both studies were carried out in France, Germany, Spain, Sweden and the Ukraine and the adult Study in the United Kingdom. The Applicant states that These studies have been designed and performed in accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) Guidance Documents.; the Applicant then lists/references the following Notes for Guidance/Points to Consider documents:


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• Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma (CPMP/EWP/2922/01).

• Points to Consider on the Requirements for Clinical Documentation for Orally

Inhaled Products (OIP) (CPMP/EWP/4151/00).

• Points to Consider on Switching between Superiority and Non-Inferiority (CPMP/EWP/482/99).

• CPMP Note for Guidance: Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products III/5378/93-Final.

The primary objective of both pivotal efficacy studies was to demonstrate the non-inferiority of the SkyePharma HFA pressurised metered dose inhaler/budesonide HFA pMDI when compared with the AstraZeneca CFC pressurized metered dose inhaler/budesonide CFC pMDI over a 12-week treatment period, at two dose levels in the adult studies (400µg per day and 800µg per day) using both strengths of budesonide HFA pMDI, budesonide 100µg and budesonide 200µg per actuation, and at one dose level in the study in children (400µg per day) using the lower strength budesonide HFA pMDI, budesonide 100µg per actuation. Secondary objectives in both studies were to determine if budesonide HFA pMDI (in both strengths in the adult study) is comparable with budesonide CFC pMDI in the assessment of clinical endpoints of function and of symptomatology and to compare the safety of budesonide HFA pMDI (at both dose levels in the adult study) with budesonide CFC pMDI assessed through the incidence of treatment emergent adverse events and changes in vital signs and clinical laboratory tests. The study in children also included as secondary objectives a comparison of the pharmacokinetics of budesonide HFA pMDI with budesonide CFC pMDI when administered in a single dose of 200µg in a subgroup population and a comparison of the systemic effects of the two formulations of budesonide on the HPA axis through urinary measures in a subgroup population. With the exception of the study of two dose levels in the adult study and the choice of primary efficacy endpoints in the two studies, the two pivotal efficacy studies were of very similar design.


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The design of the studies is summarised in the table below:


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In both studies the dose selected was based on the current GINA Guidelines for the treatment of asthma. In the adult study patients with a forced expiratory volume in one second (FEV1) per cent predicted between 81 and 90% received low dose budesonide, 400µg per day (2x100µg twice daily) and patients with a FEV1 per cent predicted between 50% and 80% received the higher dose regimen of 800µg per day (2x200µg twice daily); in the study in children, children recruited recorded a FEV1 per cent predicted of > 60% and all children received budesonide in a dose of 400µg per day (2x100µg twice daily). The primary efficacy variable in the adult study, Study SKY2021-002 was the change in mean morning peak expiratory flow rate (PEFR) from the baseline visit (week 0) to week 12 (or the final visit for those patients discontinuing the study prior to the end of week 12). This variable was chosen as the primary endpoint as it is a reliable, reproducible and convenient test that can be performed daily at home by the patient. It is also thought to provide a more complete assessment of asthma over time as opposed to single measurements at 2 or 4-weekly intervals during the treatment period. It is also noted that an electronic diary system was used in this study which permitted the validation of the timing of the daily PEFR measurements by the patient by preventing any recording of PEFR data beyond the specific study day and time window. In the study in children, Study SKY-2021-003 the primary efficacy variable chosen was the mean percentage change in FEV1 from the baseline visit to week 12, measured in the clinic, (in preference to PEFR) as it was deemed that reliable spirometry results can be obtained in the clinic under supervision whereas measurements of PEFR at home can be somewhat unreliable in childhood asthma unless well supervised by the parent or carer. Secondary efficacy endpoints in both studies included other measures of pulmonary function, frequency of exacerbations of asthma and data recorded in the electronic diary, evening PEFR (and morning PEFR in children), use of rescue salbutamol pMDI, asthma symptom scores and sleep disturbance scores. The duration of the run-in period in both studies varied and was either up to 2 weeks or up to 4 weeks depending on whether the patient was steroid-requiring or steroid-naïve on entry to run-in period. The run-in period assessed the eligibility of the patient to progress to the randomised 12-week treatment period, eligibility based on a need for rescue salbutamol pMDI and asthma symptoms – a requirement for two or more inhalations of salbutamol per day for at least three days, at least one night with sleep disturbance or at least three days with asthma symptoms.

At randomisation adult patients at each dose level were stratified within each treatment group according to their prior steroid use, i.e. steroid-requiring or steroid-free, and were randomised to receive either budesonide HFA pMDI or budesonide CFC pMDI.


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With the exception of rescue salbutamol pMDI for use as needed to control asthma symptoms, all asthma medication was withheld, bar study medication, for the duration of the 12-week treatment period. The findings in the two pivotal efficacy studies were as follows: Study No: SKY2021-002 – The adult study recruiting from age 12 years and above The demographic and baseline characteristics in the PP Population were reasonably well matched between the four treatment groups although it is noted that in the budesonide CFC pMDI 400µg per day treatment group only one patient recruited fell within the 12-18 year age band (aged 18 years) and only one patient in this treatment group was aged 65 years or greater. It is also noted that in the two treatment group inhaling the lower dose regimen (400µg per day) there would appear to be a preponderance of females approximately 70% of the total patient pool; however this difference in male to female recruitment essentially disappeared in the treatment groups receiving the higher dose regimen (800µg per day). A total of 381 patients were enrolled into the run-in period and 322 were randomised to treatment of whom 321 were included in both the Safety Population and the Full Analysis Set (one patient was withdrawn following a randomisation error having not received any study medication). A total of 274 patients were included in the PP Population. The age range of patients in the Full Analysis Set ranged from 12-77 years in the budesonide HFA pMDI treatment group and from 12 to 76 years in the budesonide CFC pMDI treatment group. In general there was fairly good representation of all age groups across the treatment groups but with the exception of the two age bands highlighted above. It is noted that less patients in the younger age bands received the higher dose regimen and a greater number in the older age bands received the higher dose regimen when compared with those receiving the lower dose regimen. In the higher dose regimens seven patients were aged between 12 and 18 years and 26 were aged 61 years and above; in the lower dose regimens 17 patients were aged between 12 and 18 years and 11 were aged 61 years and above.

Only four out of 274 patients in the PP Population were non-White/non- Caucasian. The majority of patients recruited were steroid-requiring prior to entry into the study with only 50 out of 274 patients in the PP population steroid-naïve on entry to the study. The majority of patients (266 out of 274) had no prior use of long-acting ß2 agonists prior to entry into the study. A total of 281 (87%) patients completed the study, 41 (13%) were withdrawn. Of the withdrawals 12 were withdrawn due to an adverse event and 11 due to lack of efficacy; these 23 withdrawals were fairly evenly split across the four treatment groups.


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The table below shows the patient disposition in the two pivotal studies:

The findings in respect of the primary efficacy variable are presented in the table below:

The findings demonstrate an increase in pulmonary function in all four treatment groups, both the budesonide HFA pMDI treatment groups and both the budesonide CFC pMDI treatment groups in respect of the primary efficacy variable, the change in mean morning PEFR from baseline to week 12 (or final visit) of the study. Non-inferiority was demonstrated for both dose regimens as the upper limit of the 95% CI for the least square mean difference between budesonide HFA pMDI and budesonide CFC pMDI was < 20 L/min in both analysis populations (the PP Population and the Full Analysis Set).


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The figure below shows the change from baseline in mean morning PEFR over the 12-week study:

The finding from the analyses of the secondary variables supported the analysis of the primary variable and no statistically or clinically significant differences between budesonide HFA pMDI and budesonide CFC pMDI were demonstrated between the treatment groups at either dose level for any variable in either analysis population. The only secondary efficacy variable where a difference was seen between two treatment groups, although not a statistically significant treatment difference, was evening PEFR, where the increase from baseline to week 12 was greater in the budesonide CFC pMDI treatment group than in the budesonide HFA pMDI treatment group for the lower dose regimen, with differences of 17.6L/min compared with 5.0L/min for the two treatments, respectively (PP Population). However, this difference was not seen in the analysis of evening PEFR in the higher dose group, with increases of 9.1 L/min and 10.2 L/min in the two treatment groups, respectively (PP Population). The primary and secondary efficacy endpoints were evaluated in both analysis populations, the PP Population and the Full Analysis Set. The conclusions from the analyses were the same for all endpoints regardless of the population analysed. A sub-population analysis from the PP Population was also carried out for both morning and evening PEFR measurements excluding data recorded within 6 hours of inhaling rescue salbutamol. The findings were similar in the analyses carried out in this sub-population to those seen in the analyses of the full PP Population. In the PP Population the frequency of asthma exacerbations, measured as the percentage of patients with at least one asthma exacerbation, was similar across the four treatment groups. For the lower dose regimen (400µg per day) 63% of patients in the budesonide HFA pMDI compared with 57% of patients in the budesonide CFC pMDI treatment group reported at least one asthma exacerbation; in the higher dose regimen (800µg per day) the difference between treatment groups was reversed with 51% of patients in the budesonide HFA pMDI UKPAR AstraZeneca UK Ltd, Pulmicort CFC-free Inhalers 100 and 200 micrograms

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compared with 56% of patients in the budesonide CFC pMDI treatment groups reporting at least one asthma exacerbation. The differences between the two treatment groups at each dose level were not statistically significant. The majority of exacerbations were described as mild/moderate; two patients receiving budesonide CFC pMDI and one receiving budesonide HFA pMDI reported a severe asthma exacerbation defined as asthma deterioration requiring additional medication further to any rescue salbutamol.

The Applicant concludes that budesonide formulated with propellant HFA-134a and administered at two dose levels demonstrates equivalent asthma control when compared with budesonide formulated with CFC propellants administered at the same dose levels, demonstrating the non-inferiority of budesonide HFA pMDI when compared with budesonide CFC pMDI within each dose group. A similar response over the 12-week treatment period was observed for both formulations and without any indication of tolerance. However the Applicant does note that the persistence of efficacy beyond the duration of the study was not evaluated but comments that other studies with inhaled budesonide do not indicate that long-term use is associated with tolerance.

Study No: SKY2021-003 – The study in children aged between 6 and 12 years The demographic and baseline characteristics in the PP Population were well matched between the two treatment groups. A total of 195 children entered the run-in period of whom 159 were randomised to receive one of two study treatments. The mean age of the study population was similar in the two treatment groups, 9.8 years (SD 1.94) in the budesonide HFA pMDI and 9.3 years (SD 1.81) in the budesonide CFC pMDI treatment groups (range over the entire study 6-12 years). When the population of children receiving each treatment is broken down into 12 month age groups the distribution across the age groups is good; however, a higher percentage of older children were randomised to receive budesonide HFA pMDI compared with a slightly higher percentage of younger children randomised to receive budesonide CFC pMDI. Out of the total PP Population of 151 children only 5 were non/White non/Caucasian. Two thirds of the study population were male. In the PP Population approximately 50% were steroid-requiring prior to entry into the study, the remainder being steroid-naïve; the majority of the children recruited had no prior use of long-acting ß2 agonists, 85% randomised to the budesonide HFA pMDI treatment arm and 93% randomised to the budesonide CFC pMDI treatment arm. A total of 159 children were randomised study treatments, 77 receiving budesonide HFA pMDI and 82 receiving budesonide CFC pMDI; all 159 patients were included in the safety analysis, 157 were included in the Full Analysis Set and 151 patients were included in the PP analysis. A total of 149 patients (94%) completed the study, 10 (6%) were withdrawn; 4 discontinued due to an adverse event (2 in each treatment group), and one patient discontinued the study due to lack of efficacy (in the budesonide CFC pMDI treatment group). See table above in respect of patient disposition for Study SKY2021-003. This study in children was stratified for use of a spacing device and the device used was the AstraZeneca NebuChamber. This spacing device is a 200mL pear-shaped non-electrostatic stainless steel spacing device with a detachable mouthpiece to facilitate drug administration via a pMDI. The silicone membranes in the mouthpiece assure unidirectional airflow from the spacing device without adding any dead space in the inspiratory channel. A greater percentage of patients used a spacing device to administer study drug in each treatment group compared with those who did not use a spacing device – in patients receiving budesonide HFA pMDI 60 patients (78%) used the device and 17 patients (22%) did not; in patients


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receiving budesonide CFC pMDI 62 patients (78%) used the spacing device and 18 patients (23%) did not. The findings in respect of the primary efficacy variable are presented in the table below:

In the PP Population mean FEV1 values at baseline were 1.779L in the budesonide HFA pMDI treatment group and 1.724L in the budesonide CFC pMDI treatment group and by week 12 increases in FEV1 to 2.029L and 1.923L were seen in the two treatment groups, respectively. From baseline to week 12 the mean percentage change in absolute FEV1 was +16.2% and +13.3% in the budesonide HFA pMDI and budesonide CFC pMDI treatment groups, respectively. The estimated difference between treatments (budesonide CFC pMDI – budesonide HFA pMDI) was - 2.6% (95% CI - 7.6 - 2.4). The findings in the analysis of the Full Analysis Set were similar. As the upper limit of the 95% CI of the estimated difference was < 10% (the pre-defined non-inferiority limit set) non-inferiority of budesonide HFA pMDI to budesonide CFC pMDI was deemed to have been shown in respect of the primary efficacy variable.


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The figure below shows the average percentage change from baseline in FEV1 at each clinic visit:

The graph clearly shows the initial improvement in pulmonary function from baseline during the first two weeks of the treatment period, an improvement which is maintained over the 12-week treatment period. The findings from the analyses of the secondary efficacy variables mirrored the findings in respect of the primary efficacy variable. Improvements were seen in pulmonary function and in the assessment of symptoms, sleep disturbance and use of rescue salbutamol in both treatment groups over the 12-week treatment period with no statistically significant differences seen between treatment groups. A total of 34 children (45%) and 33 children (43%) in the budesonide HFA pMDI and budesonide CFC pMDI treatment groups, respectively, reported at least one asthma exacerbation. In the PP Population all exacerbations were mild to moderate in severity. One child receiving budesonide CFC pMDI in the Full Analysis Set reported a severe asthma exacerbation. As in the adult Study SKY2021-002 sub-population analyses were carried out. Morning and evening PEFR data were re-analysed for the PP Population excluding data recorded within 6 hours of inhalation of rescue salbutamol and as in the previous study similar results were seen between the two treatment groups. The study in children was stratified for use of a spacing device and in this study FEV1 was evaluated separately for children using a spacing device and children not using a spacing device. The spacing device used in the study was the AstraZeneca NebuChamber. For FEV1 at week 12 the upper limit of the 95% CI of the estimated difference between the treatment groups was < 10% for both patients who used a spacing device (estimated least square difference of -4.075 and 95% CI of -9.924 – 1.773) and children who did not use a spacing device (estimated least square difference of 0.057 and 95% CI of - 8.210 – 8.325). The Applicant concludes that there were no statistically significant differences seen in FEV1 between the two treatment groups for patients who used a spacing device and patients who did not use a spacing device. In the group using spacing device the increase in morning PEFR from baseline to week 12 was similar between treatment groups – budesonide HFA pMDI +33.7L/min compared with budesonide CFC pMDI +34.4L/min – with an estimated difference of 0.8L/min (95% CI 12.7-14.4). The increase in morning PEFR in those children


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not using a spacing device differed between the two treatment groups – budesonide HFA pMDI +22.9L/min compared with budesonide CFC pMDI +40.7L/min – with an estimated difference of 17.5L/min (95% CI -3.2 – 38.3). The Applicant comments that the larger estimated difference in morning PEFR in the treatment groups who did not use a spacing device compared with those who did may be due to the smaller patient group not using a spacing device, approximately 20% of the total study population, and hence the larger variation in response to treatment. The Applicant concludes that overall non-inferiority has been demonstrated between budesonide HFA pMDI and budesonide CFC pMDI when budesonide is administered in a total daily dose 400µg over a treatment period of 12 weeks. The Applicant also comments that the findings are independent of the use of a spacing device.

3.3 Studies in special populations – children

One pivotal study, Study SKY2021-003 has been carried out in children aged between 6-12 years. This study is described above at 3.2 Pivotal efficacy studies.

3.4 Ongoing studies

The Applicant makes no comments in respect of ongoing studies. 3.5 Statistical Assessor’s comment (October 2006)

Two studies have been submitted as pivotal evidence of efficacy in these applications. Study SKY2021-002 (adults and adolescents) and SKY2021-003 (6-12 year olds) are described in detail in section 3.2 of this report. Both of these studies have been appropriately analysed and there are no major methodological concerns. The studies provide good evidence that budesonide HFA pMDI is non-inferior to budesonide CFC pMDI. The only potential problem is that due to the dose response relationship of inhaled corticosteroids similar improvements to those seen would be expected with higher doses of budesonide. Therefore, it would be unlikely that these studies could identify that the new formulation was more potent that the CFC formulation. Hence it remains possible that the new formulation is more potent on the basis of the clinical studies taken in isolation. However, some reassurance on this possibility is provided by Study SKYE 2021-01 as only slightly higher systemic levels of budesonide were seen following budesonide HFA pMDI and these fell within reasonably tight limits of 0.80-1.25. If there are no pharmaceutical concerns over the HFA formulation being more potent than the CFC formulation the studies submitted may be considered sufficient to establish a positive benefit risk relationship for the HFA formulation. If some concerns are present then the comparative safety data available on the two formulations would be crucial in providing reassurance on this issue.

It should also be noted that the Applicant has investigated the effect of a spacing device in the paediatric study appropriately and similar efficacy in the two treatment groups is observed in subjects who have and who have not used a spacing device.

3.6 Clinical Assessor’s comment (October 2006)

The clinical programme submitted with these applications has been designed to demonstrate non-inferiority of budesonide HFA pMDI when compared with budesonide CFC pMDI in both adults and adolescents with asthma and in children aged 6 to 12 years with asthma through two separate pivotal clinical studies. Each study compared the efficacy and safety of budesonide in the two formulations over a 12-week treatment period. The study in adults compared the two formulations at 2 dose levels, 400µg and 800µg per day, using both


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strengths of budesonide HFA pMDI, budesonide 100µg and budesonide 200µg per actuation, the study in children compared the formulations at one dose level, 400µg per day, using the lower strength budesonide HFA pMDI, budesonide 100µg per actuation. The major differences between the two studies are the population of patients studied, the use of both strengths of budesonide HFA pMDI in the study in adults and the choice of primary efficacy variable in the two studies. The studies shared the same objectives, the primary objective being to demonstrate the non-inferiority of budesonide HFA pMDI when compared with budesonide CFC pMDI and secondary objectives to determine whether budesonide HFA pMDI is comparable with budesonide CFC pMDI in the assessment of clinical endpoints of function and of symptomatology and to compare the safety of the two formulations of budesonide in the two populations. The efficacy variables (primary plus secondary) were the same in both studies, however, the primary efficacy variable did differ between studies; in the study in adults the primary variable was the change in mean morning PEFR from baseline to week 12 measured daily at home by patients, in the study in children the primary variable was the mean percentage change in FEV1 from baseline to week 12 measured in the clinic. The Applicant discusses the reasons behind this difference in primary efficacy endpoints in these two studies and these are acceptable (see Point 3.2, above). The study in children was stratified for use of a spacing device and the device used in the pivotal study was the AstraZeneca NebuChamber (described at Point 3.2, above). The majority of children, 78% in each treatment group, used this spacing device. The two studies were appropriately designed, had appropriate endpoints and were appropriately analysed. However, it might be argued that the non-inferiority margins were somewhat wide and that these should be justified. Both studies were active-controlled studies and without a placebo treatment arm and by ensuring a baseline level of symptoms and less than optimal pulmonary function on current treatment at randomisation to study treatments, populations of adults and children in whom there was room for improvement in asthma control would be studied. Therefore if there were clinically important differences between study treatments in respect of efficacy these entry criteria would provide an increased likelihood of these differences being detected and hence enhance the sensitivity of study.

The comparisons of budesonide HFA pMDI with budesonide CFC pMDI at two dose levels in the adult study and at one dose level in the study in children demonstrate non-inferiority in respect of asthma control. Both primary and secondary efficacy variables were evaluated in both analysis populations, the PP Population and the Full Analysis Set, and with the exception of one secondary efficacy variable in the adult study, evening PEFR where a difference, although a non-statistically significant difference, was seen with a greater increase in evening PEFR from baseline to week 12 in the budesonide CFC pMDI treatment group than in the budesonide HFA pMDI treatment group for the lower dose regimen, the conclusions from all analyses for all endpoints were similar regardless of the population analysed and confirmed non-inferiority. However in the light of the known fairly flat dose-response curve seen with inhaled corticosteroids, similar improvements in pulmonary function might be seen with higher dose regimens of budesonide and therefore the possibility that this new CFC-free formulation of budesonide might be superior in respect of efficacy to the original CFC-containing formulation cannot be ruled out. The stratification for use of a spacing device in the study in children produced very unequal treatment groups with 78% of children randomised to treatment using a spacing device. There appeared to be no statistically significant differences in FEV1 between the two treatment groups for patients who used a spacing device and patients who did not use a spacing device, although the increase in morning PEFR in children not using a spacing device did differ between the two treatment groups. This might be due to the smaller size of the patient group


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(approximately 20% of a total study population) and hence the larger variation in response to treatment. These findings would suggest that in a population of patients who would normally use a spacing device with a pressurised metered dose inhaler there would appear to be no difference between the 2 treatments, and that the overall conclusion drawn from this study, that budesonide formulated with propellant HFA-134a provides equivalent asthma control when compared with budesonide formulated with CFC propellants and when administered at the same dose, would apply to the sub-population in whom the drug was delivered via a pressurised metered dose inhaler with spacing device (the NebuChamber spacing device).

It is of note that only 24 patients randomised to treatment in the adult study were aged between 12 and 18 years. However, in light of the well–known efficacy and safety of budesonide and the findings of the second pivotal efficacy and safety study in children, the recruitment of only few adolescents should not preclude an authorisation for use of this CFC-free formulation of budesonide in these young adults. In conclusion the clinical studies presented in respect of efficacy demonstrate that budesonide formulated in an excipient mix including the non-CFC propellant, HFA-134a, is non-inferior to budesonide formulated in an excipient mix including CFC propellants, Pulmicort Inhaler CFC-containing, the Applicant’s original product, in the treatment of adults, adolescents and children aged between 6 and 12 years with asthma. However, the possibility that this new CFC-free formulation of budesonide might be superior to the CFC-containing formulation in respect of efficacy cannot be ruled out entirely. When a pressurised metered dose inhaler is administered to a child it is recommended that it be used in combination with a spacing device and the study in children presented confirms that the NebuChamber spacing device is an acceptable device and as such should be named within the product literature. For further discussion and resolution of this point see page 57.

4. CLINICAL SAFETY 4.1 Overview/Exposure

The clinical programme presented in the dossier includes two pivotal clinical studies, Studies SKY2021-002 and SKY2021-003, and two clinical pharmacology studies, Studies SKYE 2021-01 and SKY2021-004. All four studies are described above in Sections 2 and 3 of this Report. Budesonide formulated in an excipient mix including CFC propellants and delivered via a pressurised metered dose inhaler has been marketed since 1981, is approved in more than 70 countries worldwide and is available in three strengths, 50, 100 and 200 micrograms per actuation pressurised inhalation suspension. Clinical trials with budesonide as both a pressurised inhalation suspension and as a dry powder formulation have involved over 61,000 patients and healthy volunteers and post-marketing experience includes more than 11 billion patient treatment days. All patients randomised to study treatments and who received any study medication were included in the Safety Populations. A total of 342 subjects/patients were exposed to budesonide HFA pMDI and 345 subject/patients were exposed to budesonide CFC pMDI. It is of note that in three of the four studies, the single dose pharmacokinetic study, Study SKYE 2021-01 and the two pivotal clinical studies, all subjects/patients received both non-CFC (HFA-134a) and CFC propellants; the Phase 1 study employed a crossover design and in order to maintain study blindness in the pivotal clinical studies patients in both treatment


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groups received both propellants – one in the active formulation and one in the placebo formulation. The double blind study design in the pivotal clinical studies will reduce bias, however use of this design with all patients inhaling both CFC-free and CFC-containing propellants does make the assessment of the safety profile of budesonide HFA pMDI compared with budesonide CFC pMDI more complex. Study SKY2021-004 used an open-label design and following the run-in period subjects were randomised to receive either budesonide HFA-pMDI or budesonide CFC-pMDI (without placebos and hence without inhalation of the alternative propellant). The Applicant does state that the data from this study should be considered more definitive and supportive of the safety of budesonide formulated with propellant HFA-134a.

In the two clinical pharmacology studies in healthy volunteers, single doses up to 1600µg were studied in one (n=40) and a dose of 800µg twice daily for four weeks in the other (n=48); in the clinical efficacy and safety studies doses of 200µg twice daily and 400µg twice daily over a 12-week treatment period were studied in adult patients with asthma (n=322) and doses of 200ug twice daily over a 12-week treatment period were studied in children with asthma (n=159). Only one study saw the recruitment of children, Study SKY2021- 003, with randomisation of 159 children aged between 6 and 12 years. The assessment of safety has been based on an evaluation of the incidence of treatment emergent adverse events, changes in vital signs and clinical laboratory tests, and in the clinical pharmacology studies and in the study in children an assessment of systemic effects on the HPA axis through measurement of plasma and urinary cortisols. The Applicant’s overview of the safety data generated in this clinical programme is presented in the Clinical Overview.

4.2 Adverse Events

Summary tables of adverse events across the four studies in respect of numbers of adverse events, severity of adverse events and relationship to study drug and in respect of the most common adverse events reported, are presented in the Clinical Overview, Appendix 5-2, Tables 2.5.9 and 2.5.10. The number of subjects/patients reporting adverse events in each of the four studies was similar across the two treatment groups within each study, the majority of events reported were described as mild to moderate in severity and were not deemed by the clinical investigators to be related to study treatments. The Applicant does comment on the high incidence of adverse events deemed to be related to study treatment in the multiple dose clinical pharmacology study, Study SKY2021-004 and gives no reason for this high incidence of treatment related events other than to comment that the study was carried out in a single centre and all events were assessed by a single investigator. There were no real differences between study treatments in each of the four studies in respect of the reporting of specific adverse events and the most common events reported were those of nasopharyngitis, respiratory tract infections, pharyngolaryngeal pain and headache. Further to the above listed adverse events dyspepsia, dry lips, nausea and vomiting were reported in the multiple dose clinical pharmacology study, Study SKY2021-004 each in 13% or more of the study population, but for all adverse events reported in this study, where reports did appear to be higher than in the other three studies, the incidences were generally higher in the budesonide CFC pMDI treatment group. It is this multiple dose clinical pharmacology study which provides the direct comparison (open-label) of budesonide HFA pMDI with budesonide CFC pMDI and although the reporting rate for adverse events does appear higher than in the other studies, there were no adverse differences seen between the two formulations of budesonide over the 4-week treatment period and there appeared to be no increased


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incidence of local adverse events after switching from the CFC-containing formulation to the CFC-free formulation. The incidence and type of local adverse events were comparable. No unexpected adverse events were reported in any study.

The relatively high incidence of nasopharyngitis and headache is commented on in section 4.10.

Nasopharyngitis and headache do not feature in the SPCs for the CFC-containing pressurised metered dose inhalers or the dry powder formulations of budesonide and therefore in the light of the high incidence of these events seen in the studies presented consideration should be given to including these events within the SPC, Section 4.8 for both strengths of this new CFC-free pMDI (consideration should also be given to the inclusion of these adverse events in the SPCs for other formulations of budesonide). Note to reader: For Applicant’s response and resolution please see page 59 . No deaths occurred in any study.

Four serious adverse events were reported in the adult clinical efficacy and safety study, Study SKY2021-002, three in patients receiving budesonide HFA pMDI and one in a patient receiving budesonide CFC-pMDI. None was considered by the investigators to be related to study treatments and with the exception of one patient receiving budesonide HFA pMDI reporting a severe asthma exacerbation, three of the four patients completed the study. Six patients in each treatment group in the adult clinical study discontinued the study due to an adverse event, only one of these, a severe headache reported by a patient receiving budesonide CFC pMDI was deemed related to study treatment. In the study in children, Study SKY2021-003 two children in each treatment group discontinued the study due to an adverse event (asthma exacerbation in each case) but none was considered related to study treatment.

4.3 Class effects

The incidence of the common glucocorticosteroid-related adverse effects, which include hoarseness, dysphonia, cough and oral candidiasis, was generally low. Oral candidiasis was reported in the clinical efficacy and safety study in adults, Study SKY2021-002, three patients had evidence of oral candidiasis at the final visit, two patients in the budesonide HFA pMDI treatment group and receiving 800µg per day and one patient in the budesonide CFC pMDI treatment group receiving 400µg per day. Effects on the HPA axis were measured in three of the four studies, plasma cortisol was measured in the single dose pharmacokinetic study, Study SKYE 2021-01 and urinary cortisol/creatinine ratio (UCC) following collection of the 12-hour overnight urine was measured in the multiple dose pharmacodynamic study, Study SKY2021-004 and in the clinical efficacy and safety study in children, Study SKY2021-003. The 12-hour overnight urine is accepted as a measure of HPA axis function although it should be noted that current recommendations in respect of the measurement of systemic effects would request that the 24-hour urine collection be used rather than the 12-hour overnight collection.

In both of the studies in healthy volunteers there is a suggestion of a slightly enhanced systemic effect with budesonide formulated with propellant HFA-134a (budesonide HFA pMDI) with lower plasma cortisol levels seen following the administration of 1600µg in the first study and a greater fall in urinary cortisol/creatinine ratio over four weeks treatment with a dose of 800µg twice daily in the second study. In this study this difference between the two formulations was statistically significant when all data were included in the analysis; however, the removal of one subject from the budesonide CFC pMDI treatment group in


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whom data collected were described as extremely variable, did reduce this statistically significant difference between treatments to a non-statistically significant difference. Numerically lower UCC levels were seen in the budesonide HFA pMDI treatment group compared with the budesonide CFC pMDI treatment group. The clinical significance of the findings is difficult to assess and further review alongside the findings in respect of systemic exposure in the pivotal efficacy studies is required. In the study in children there were no patients in the budesonide HFA pMDI treatment group with urinary data at both baseline and week 12/final visit and therefore changes from baseline to the end of the treatment period in respect of UCC could not be calculated.

4.4 Vital signs

No statistical differences were seen between treatments in either of the two clinical pharmacology studies or in the two clinical efficacy and safety studies in respect of vital signs.

4.5 Laboratory Data

There appeared to be no important differences in respect of laboratory variables across treatment groups in either of the two clinical pharmacology studies or in the adult clinical efficacy and safety study (laboratory data were not collected in the clinical efficacy and safety study in children).

4.6 Safety in special populations 4.6.1 Safety in children

See Sections 4.1, 4.2, 4.3 and 4.4 above The pivotal clinical study, Study SKY2021-003 saw randomisation of 159 children aged 6 to 12 years, of whom 77 received budesonide HFA pMDI and 82 received budesonide CFC pMDI.

The pivotal clinical study in adults, Study SKY2021-002 saw randomisation of 24 adolescents aged 12 to 18 years, of whom 13 received budesonide HFA pMDI and 11 received budesonide CFC pMDI.

4.6.2 Elderly

Out of a total 274 patients in the PP Population in the adult clinical efficacy and safety study, Study SKY2021-002 only 16, of whom 12 inhaled the higher dose regimen of 400µg twice daily and 4 inhaled the lower dose regimen of 200µg twice daily, were aged 65 years or over. Safety has not been reviewed specifically in this age group and the breakdown of adverse events across treatment groups in patients 65 years of age and older is not presented.

4.6.3 Pregnancy and lactation

The safety of budesonide HFA pMDI in pregnancy and lactation was not investigated in the studies presented in the dossier. All studies specifically excluded female patients who were either pregnant or breast-feeding. However, the Applicant does state that based on the world-wide post-marketing experience with budesonide, no adverse events of inhaled budesonide with HFA pMDI during pregnancy on the health of the fetus/newborn child are expected. …… Pulmicort has a pregnancy rating of Category B (the first and only inhaled corticosteroid to receive this rating from the United States Food and Drug Administration), indicating that


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Pulmicort is an effective option for helping to control asthma during a woman’s pregnancy. However, it should be noted that budesonide formulated in an excipient mix including the non-CFC propellant HFA-134a has not been administered to pregnant or lactating females humans to date although studies of HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special risk.

4.7 Safety related to drug-drug interactions and other interactions

Specific interactions studies were not performed. 4.8 Data from ongoing studies

The Applicant makes no comment in respect of ongoing studies. 4.9 Post-marketing data

No post-marketing experience exists with budesonide formulated as a pressurised inhalation suspension and with the non-CFC propellant, the hydrofluoroalkane propellant HFA-134a. The CPMP Note for Guidance: Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products III/5378/93-Final (Appendix 5-1) requests that applications for Marketing Authorisations for metered dose inhalation products containing propellant HFA-134a should include proposals to monitor the introduction of the new non-CFC products in order to identify rare and unexpected adverse events. A method such as the use of record linkage schemes should be considered as these could provide a means for prospectively monitoring new non-CFC propellants against historical data relating to the products using CFC propellants – see Paragraph 4.2.1 of Appendix 5-1. The Applicant has not submitted proposals for post-marketing surveillance of these new non-CFC inhalers and therefore such proposals will be requested. A definitive proposal for a Phase IV study with the identifiable proprietary product, in accordance with the CPMP Note for Guidance, must be presented and agreed before Marketing Authorisations are granted. The study proposal should be for either an observational cohort study or a blinded trial which has the capability of generating data on the general safety profile of the new products. Assessments of the incidence of paradoxical bronchospasm, worsening asthma and cough must be incorporated into the design of the study.

The Applicant makes no mention of the requirement for post-marketing surveillance of the new inhalers formulated with propellant HFA-134a.

4.10 Clinical Assessor’s comments (October 2006)

The safety assessment of budesonide formulated with the non-CFC propellant HFA-134a as a pressurised inhalation suspension shows a comparable safety profile to that of budesonide formulated as a pressurised inhalation suspension with CFC propellants. Both formulations appear well tolerated and no unusual or unexpected adverse events were reported in either adults or in children aged between 6 and 12 years. It should be noted that although the pivotal efficacy and safety study in adults recruited some adolescents aged 12 to 18 years the population of these young adults was small (n=24). However, in the light of the well–known efficacy and safety of budesonide and the findings in respect of safety in the second pivotal efficacy and safety study, the study in children, the recruitment of only few adolescents should not preclude an authorisation for use of this CFC-free formulation of budesonide in these young adults.


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However, two adverse events, nasopharyngitis and headache, do appear with an incidence of 4% or more and up to 12% in the two clinical efficacy and safety studies and with an incidence from 17% to 33% in the multiple dose clinical pharmacology study in patients/subjects receiving budesonide formulated with propellant HFA-134a, events which are not described in the Marketing Authorisations for the CFC-containing pressurised metered dose inhalers or the dry powder formulations of budesonide. Therefore it is proposed that these events be listed within Section 4.8 of the Summary of Product Characteristics for both strengths of this new CFC-free pressurised metered dose inhaler.

Systemic safety, as measured by cortisol suppression was not assessed specifically in the phase III study in adults. In the study in children, although an attempt was made to look at the effects of budesonide on the HPA axis through measurement of the urinary cortisol/creatinine ratio following collection of the 12-hour overnight urine in a sub-group of children randomised to study treatments, no patients in the treatment group receiving budesonide formulated with HFA-134a had urinary data at both baseline and week 12 and therefore changes from baseline to the end of the treatment period in respect of urinary cortisol/creatinine ratio could not be calculated. The effects on the HPA axis were measured in both of the clinical pharmacology studies and in both studies there is a suggestion of a slightly enhanced systemic effect with budesonide formulated with propellant HFA-134a with lower plasma cortisol levels seen following the administration of 1600µg in the first study and a greater fall in urinary cortisol/creatinine ratio over 4 weeks treatment with a dose of 800µg twice daily in the second study. In the light of these findings and the conclusions drawn in respect of clinical efficacy and the inability of the studies presented to confirm that budesonide formulated with the non-CFC propellant, propellant HFA-134a is not superior to budesonide formulated with CFC propellants (although non-inferiority of the new non-CFC formulation of budesonide when compared with the CFC-containing formulation of budesonide can be concluded) it is proposed that further studies to assess the systemic effects of budesonide formulated with propellant HFA-134a should be carried out and that these should look specifically at this new formulation when administered to children and when administered at the top of the proposed dose range.

Proposals for post-marketing surveillance of these new non-CFC inhalers have not been submitted. Proposals for such must be presented and agreed before Marketing Authorisations can be granted for these products. 5. CLINICAL EXPERT REPORT A satisfactory clinical expert report was provided by a suitably qualified person.

6. PRODUCT LITERATURE

6.1 SPC The SPC was assessed and amended and found to be satisfactory at time of grant of Marketing Authorisation. 6.2 PIL The PIL was assessed and amended and found to be satisfactory at time of grant of Marketing Authorisation. 6.3 Labelling Labelling was assessed and amended and found to be satisfactory at time of grant of Marketing Authorisation.


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7. CONCLUSIONS

7.1 Clinical pharmacology

No new data have been provided in respect of the clinical pharmacology of budesonide other than studies to demonstrate that the pharmacokinetic and pharmacodynamic profiles of budesonide formulated with propellant HFA-134a are similar to those of budesonide formulated with CFC propellants and in this regard two studies have been presented in healthy volunteers.

The findings in the first of the two studies, the single dose pharmacokinetic study suggest that the two formulations can be deemed to be bioequivalent and dose proportionality was apparent for both formulations over the dosing range of 400-1600µg.

Both studies assessed systemic safety through the effects of budesonide on the HPA axis and in both studies there was a suggestion of a slightly enhanced systemic effect with budesonide formulated with propellant HFA-134a. Lower plasma cortisol levels were seen following administration of 1600µg in the first study and a greater fall in urinary cortisol/creatinine ratio over 4 weeks treatment with a dose 800µg twice daily was seen in the second study. Numerically lower UCC levels were seen following inhalation of budesonide formulated with HFA-134a when compared with those seen following inhalation of budesonide formulated with CFC propellants. The clinical significance of these findings is difficult to assess and further studies to assess the effects of budesonide formulated with the non-CFC propellant, propellant HFA-134a in patients are required.

7.2 Clinical efficacy

The two clinical studies presented in respect of efficacy demonstrate that budesonide formulated with propellant HFA-134a as a pressurised inhalation suspension is non-inferior in respect of asthma control to budesonide formulated with CFC propellants, the Applicant’s original product and the reference product, in the treatment of adults, adolescents and children aged between 6 and 12 years with asthma. However, the possibility that this new CFC-free formulation of budesonide might be superior to the CFC-containing formulation of budesonide cannot be ruled out. Possible superiority of this new formulation in respect of efficacy is not an issue; This last wording and the next wording contradict? however if this new formulation of budesonide is superior to the original product in respect of efficacy the possibility of an increased systemic load compared with the CFC-containing formulation might result in enhanced systemic effects when the two formulations are administered at the same dose which could have adverse consequences when patients are switched from the original product to this new CFC-free formulation.

Therefore, if the clinical studies are taken in isolation it remains possible that the new CFC-free formulation of budesonide, budesonide formulated with propellant HFA-134a, may be more potent than the original CFC- containing formulation. The first of the clinical pharmacology studies, the single dose pharmacokinetic study does provide some reassurance for although generally slightly higher systemic levels of budesonide were seen following budesonide formulated with propellant HFA-134a, the 90% confidence intervals for the ratios of both AUC and Cmax fell within the predefined limits and therefore it can be stated that the two formulations, the CFC-free and CFC-containing can be deemed to be bioequivalent.


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However, the question of enhanced potency remains when the data in respect of systemic exposure are reviewed as discussed above at Point 7.1. Lower plasma cortisol levels and a greater fall in urinary cortisol/creatinine ratio are seen following the inhalation of budesonide formulated with propellant HFA-134a when compared with budesonide formulated with CFC propellants. When the pharmaceutical data are reviewed in vitro data demonstrate a higher metered and delivered dose per actuation and hence a higher fine particle dose and fine particle fraction when budesonide formulated with HFA-134a is compared with budesonide formulated with CFC propellants. The reason for this difference can be attributed to formulation factors such as a higher vapour pressure of the suspension of budesonide in propellant HFA-134a and to the effects of different valve and different actuator configurations used. The fine particle dose of budesonide formulated with HFA-134a is significantly greater than that of the reference product, budesonide formulated with CFC propellants – 27µg and 51µg for the 100µg and 200µg CFC-free products, respectively compared with 34µg for the 200µg reference product – See Quality Assessment Report Section 3.P.2.2.3 Physicochemical and biological properties of the drug product

The second pivotal efficacy study, the study in children did stratify for use of a spacing device, the NebuChamber spacing device and the findings suggest that in a population of patients who would normally use a spacing device with a pressurised metered dose inhaler there would appear to be no difference between the two study treatments, budesonide formulated with HFA-134a and budesonide formulated with CFC propellants, and that the overall conclusion drawn from the study, that budesonide formulated with propellant HFA-134a provides equivalent asthma control when compared with budesonide formulated with CFC propellants, and when administered at the same dose, applies regardless of whether the drug is delivered via a pressurised metered dose inhaler alone or via a pressurised metered dose inhaler with spacing device. It is of note that in the in vitro data presented the particle size distribution analysis shows that the spacing device selectively retained the aerodynamically larger particles, the delivered dose was significantly reduced and fine particle dose below 4.7µm increased slightly when the spacing device was used. – See Quality Assessment Report Section 3.P.2.2.3 Physicochemical and biological properties of the drug product – Effect of spacer use.

In the clinical efficacy study presented in children all children recruited to the study received budesonide in a dose of 400µg per day (2x100µg twice daily). This dose regimen falls within that requested by the Applicant in the SPC. (See Section 1.6.1, above and Appendix 5-8). The dose recommendations for use in children also state that The dose should be reduced to the minimum needed to maintain good asthma control. However, the differences between the dose and dose regimen as stated in the proposed SPCs for the CFC-free inhalers when compared with the Applicant’s original products, Pulmicort Inhaler 200 micrograms per actuation and Pulmicort LS Inhaler 50 micrograms per actuation, pressurised inhalation suspensions, concern the lower limit of the dose range for use in children. The lower dose limit for use in children is described for the CFC-containing products as 50 micrograms administered twice daily; for the CFC-free products this lower limit is described as 100 micrograms administered twice daily. It is appreciated that with the strengths of the CFC-free formulation available the lower limit of the dose range for use in children, as described for the original products, cannot be achieved. The Applicant has submitted a Clinical Expert Statement Pulmicort pMDI, dosage to children in UK and this is attached in full at Appendix 5-7. In this Statement the Applicant attempts to justify this change to the lower limit of the dose range when these products are used in children clinically through arguments in respect of the original clinical programme presented in the Marketing Authorisation Applications for the Pulmicort Inhaler CFC-containing pressurised inhalation suspensions where only one out of nine clinical studies carried out assessed efficacy of budesonide when administered in a dose of 100 micrograms per day. The


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Applicant claims that Limited efficacy was seen at the 100 microgram dose, and taking into account the limited sample size (n=19), it was concluded that 100 microgram/day was a subtherapeutic dose. Thus, the lowest currently recommended dose in the UK, 100 microgram/day is supported by limited clinical data.

Further justification of the change in the lower dose limit for use in children is argued on the basis of the lowest available strength of the CFC-free formulation being the 100 microgram per actuation strength, and therefore administration of a dose of 50 micrograms twice daily becomes impossible. It is accepted clinical practice that the dose of an inhaled steroid must always be titrated downwards to the lowest dose at which effective control of disease can be maintained. This change to the lower limit of the dose range for use in children will not permit such titration of the dose downwards to the minimally effective dose, and therefore is not acceptable. The dose and dose regimens for these new CFC-free pressurised inhalation suspensions must be identical to the dose and dose regimens of the reference products unless the change to the lower end of the dose range can be justified clinically. The final issue of concern in respect of these CFC-free pressurised metered dose inhalers is the apparent influence of storage orientation on the delivered dose. Currently the Applicant requests that the canisters be stored in a valve-down position only throughout the distribution chain and after being dispensed to the patient. When stored in the valve-up position the canister consistently shows a lower delivered dose compared with the delivered dose when stored in the valve-down position. These findings are of concern and from a clinical perspective appear somewhat impractical and are hence unacceptable (see Quality Assessment Report). It is proposed that this apparent dependency of the delivered dose on the orientation of valve storage be further investigated and an explanation for this phenomenon be provided. Efforts should be made to rectify the problem to remove the necessity for the inhalers to be routinely stored in the valve-down position by the patient.

In conclusion from the clinical data presented in respect of efficacy there would appear to be no reason why the Marketing Authorisations sought should not be granted. However when viewed in the context of the clinical pharmacology and pharmaceutical findings and without generations of safety data in respect of systemic effects in the clinical studies, this decision should be questioned. The grant of Marketing Authorisations should await the resolution of the issues outlined above. The advice of The Commission is sought in this regard.

7.3 Paediatric Development Plan

The Applicant requests use of both Pulmicort Inhaler 200 micrograms per actuation and Pulmicort Inhaler 100 micrograms per actuation in children. The Applicant provides no information on the age range covered by the term children and this should be justified. However the request for use in children is in line with the recommendations for such use of the Applicant’s original products, the CFC-containing pMDIs, Pulmicort Inhaler 200 micrograms per actuation, PL 17901/0158 and Pulmicort LS Inhaler 50 micrograms per actuation, PL 17901/0159.

The dose range requested for use in children differs from that of the Applicant’s original products and with the strengths available the lower limit of the dose range as defined for the Applicant’s original products cannot be achieved. This difference in dosing is not acceptable particularly in the light of accepted clinical practice that the dose of an inhaled steroid must always be titrated downwards to the lowest dose at which effective control of asthma can be maintained. Therefore the dose and dose regimens for these new CFC-free


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pressurised inhalation suspensions must be identical to the dose and dose regimens of the reference products unless the change to the lower end of the dose range can be justified clinically. See further discussion on page 47.

7.4 Benefit/Risk

The data presented confirm that the benefit/risk ratio for budesonide formulated as a pressurised inhalation suspension and in an excipient mix including the hydrofluoroalkane propellant, propellant HFA-134a, a non-CFC propellant is not acceptable. See Sections 7.2, 7.3 and 7.4, above.

8. CLINICAL AND PRECLINICAL ASSESSORS’ CONCLUSIONS

8.1 There is inadequate evidence of safety in adults, adolescents and children as it is not

possible to confirm that budesonide formulated in an excipient mix including the non-chlorofluorocarbon propellant/the hydrofluoroalkane propellant, propellant HFA-134a, is not superior to or more potent than the original CFC-containing formulation of budesonide, and hence there are concerns regarding greater systemic exposure. Therefore further information on the comparison of these new formulations of budesonide with the original products in respect of systemic safety is required, particularly for use in children and at the top of the recommended dose range.

8.2 The difference between the dose and regimen as stated for these CFC-free inhalers when compared with the original CFC-containing products at the lower limit of the dose range for use in children is not acceptable. The dose and dose regimens must be identical to the dose and dose regimens of the original products unless the change to the lower limit of the dose range can be justified clinically..

8.3 The product literature should recommend a specific named spacing device for use with this

new formulation of budesonide administered as a pressurised inhalation suspension. A spacing device should always be available together with a pressurised metered dose inhaler when such is prescribed for use by a child.

8.4 The non-inferiority margins in the two pivotal clinical efficacy studies were somewhat wide and should be justified.

8.5 The apparent dependency of delivered dose on the orientation of canister storage is considered to have a critical impact on the quality of the product. This should be further investigated and an explanation for this phenomenon provided. Efforts should be made to rectify the problem to remove the necessity for the inhalers to be routinely stored in the valve-down position through the distribution chain and after being dispensed to a patient.

8.6 Full details should be provided describing how clinical trial supplies used in the pivotal clinical efficacy and safety studies were stored in respect of canister orientation, throughout the distribution chain through to use during the clinical studies.

8.7 The conclusions reached following the assessment of the dossier on HFA-134a are as follows:

• In animal studies HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, when narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).

• No significant biotransformation of HFA-134a has been detected in man.


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HFA-134a was eliminated rapidly after administration and did not accumulate in the human body.

• In studies to detect toxicity, repeated high dose levels of HFA-134 have indicated that

safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.

• Studies of HFA-134a administered to pregnant and lactating rats and rabbits have not

revealed any special risk. • There were no reasons to consider HFA-134a as a potential mutagen, clastogen or

carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.

• HFA-134a did not appear to deplete the stratospheric ozone layer and its global warming potential was less than CFCs (0.22 compared with CFC-11 = 1.0).

The CPMP conclusions are set out below:

1. The Committee considered that HFA-134a of the specified quality could be a suitable alternative to CFCs currently used in the formulation of medicinal products, including metered dose inhalers for treatment of asthma.

2. Compatibility with an active substance would have to be established (cf Note for Guidance on the Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products, III/5378/93 final) – (Appendix 5-1)

3. The Committee attached great importance to having adequate reassurance on bronchial hyperreactivity and nasal ciliary problems. These issues were to be very carefully addressed in both the 3-month clinical and the post-marketing surveillance studies described in the CPMP guidance III/5378/93. (Subsequently these issues have been satisfactorily resolved).

4. Additionally, the consortium was asked to consider and report to the CPMP as soon as

possible any alternative approaches which might better address the concerns of the Committee on the effects of the new propellant on nasal ciliary problems and on bronchial hyperreactivity.

Therefore HFA-134a of the grade specified is considered a suitable replacement for CFCs in metered dose inhalers. The dose and dose regimens for both strengths of this pressurised inhalation suspension are almost identical to those of the Applicant’s original products, Pulmicort Inhaler 200 micrograms per actuation and Pulmicort LS Inhaler 50 micrograms per actuation, pressurised inhalation suspensions, PL 17901/0158 and PL 17901/0159. The difference between the dose and regimen as stated for these CFC-free inhalers when compared with the original CFC-containing products at the lower limit of the dose range for use in children is not acceptable. The dose and dose regimens must be identical to the dose and dose regimens of the original products unless the change to the lower limit of the dose range can be justified clinically. The recommendations for dosing in children do not include either an upper or a lower age limit; this should either be justified or age limits should be stated. UKPAR AstraZeneca UK Ltd, Pulmicort CFC-free Inhalers 100 and 200 micrograms

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In respect of the spacing device for use with Pulmicort Inhaler CFC-free the Applicant simply states that a spacer device is recommended to enable patients with difficulty in co-ordinating inhalation with actuation, such as infants, young children, the poorly co-operative or the elderly, to derive greater therapeutic benefit. The use of a spacer device obviates the need to co-ordinate breathing and actuation, whilst also reducing oropharyngeal absorption of budesonide. With regard to the original products, the CFC-containing products, two spacing devices are actually named as appropriate to use with the CFC-containing inhalers, the NebuChamber spacing device and the Nebuhaler spacing device. Since the late 1990s the use of a spacing device with a pMDI has formed a part of the licencing process with the inclusion of statements within the Summaries of Product Characteristics and the Patient Information Leaflets, and latterly also in the product labelling, to advise that a spacing device can/should be used with the product; such a device must be a specific named device. It is expected that all applicants submitting applications for pMDIs should provide data in support of such a device and this will include both in vitro and in vivo data. The spacing device is used with a pMDI for a number of different reasons from being an aid to inhalation for those patients who find it difficult to synchronise actuation of the pMDI with inspiration of breath to reasons of safety through the reduction of the amount of drug which ends up in the mouth and throat which is swallowed and subsequently absorbed into the systemic circulation via the gastrointestinal tract. However, as the route of absorption of inhaled corticosteroids differs depending on the active the use of a spacing device when inhaling, a corticosteroid will have differing effects on the systemic load and hence on the occurrence of systemic events. It is also appropriate that a spacing device is always available together with the pMDI when such is prescribed for use by a child. Guidance on the data required to support the use of a spacing device with an inhaled product is provided in the following CHMP Guidelines:

• Points to Consider on the Requirements for Clinical Documentation for Orally

Inhaled Products (OIP), CPMP/EWP/4151/00

• Note for Guidance on Requirements for Pharmaceutical Documentation for Pressurised Metered Dose Inhalation Products, CPMP/QWP/2845/00

• the Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products,

EMEA/CHMP/QWP/49313/2005. The inclusion of instructions on the use of a specific spacing device in the SPC is implied in the CPMP/QWP/2845/00 Guideline but is more robustly stated in the EMEA/CHMP/QWP/49313/2005 Guideline released for consultation in January 2005 and currently awaiting adoption by CHMP. The three CHMP Guidelines listed above are presented in Appendix 5-3. It should also be noted that the NICE Guidance on inhaler devices for children with chronic asthma states that:

• For children under 5 years of age corticosteroid and bronchodilator therapy should

be delivered by a pressurised metered dose inhaler and spacer device, with a facemask if necessary,

and that


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• For children aged 5 – 15 years corticosteroid therapy should be routinely delivered by a pressurised metered dose inhaler and spacer device.

Furthermore both the British Guideline on the Management of Asthma (British Thoracic Society and Scottish Intercollegiate Guidelines Network) revised edition April 2004 and the Global Strategy for Asthma Management and Prevention – Global Initiative for Asthma (GINA) updated 2003 both recommend the use of spacing devices.

Therefore the Applicant will be required to carry out the appropriate in vitro and in vivo studies to support a spacing device for use in both adults and children such that this device can be named in the Summaries of Product Characteristics and in the Patient Information Leaflets. In addition the clinical assessor requested changes to the SPC and product literature and a satisfactory SPC and PIL were arrived at during the assessment process.


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COMMITTEE ON SAFETY OF MEDICINES RECOMMENDATIONS AND ASSESSMENTS OF APPLICANT RESPONSES The applications were considered by the Commission on Human Medicines on 22/06/2006, 14/03/2008 and 19-26/06/2008. The information contained in this part of the Public Assessment Report concentrates on the resolution of major issues which led to the granting of the Marketing Authorisations.

Main Pharmaceutical Points 1 The issue with the effect of orientation dependency on delivered dose is

considered to be major/critical as it would be very difficult to ensure patient compliance in this respect.

Company Response provided March 2007

The drug product is provided with a metering retention valve for dose delivery. Prior to actuation an aliquot of formulation is retained in the metering chamber of the valve. When the valve stem is depressed during the actuation cycle the exit orifice in the valve stem enters the metering chamber of the valve just below the second gasket. The differential pressure between the metering chamber and environmental pressure results in release of formulation to the patient. Once an actuation has been delivered, the valve stem is returned to its resting position and the metering chamber is refilled via a capillary channel leading to the bulk suspension. The suspension is then retained in the metering chamber until subsequent use by the patient. However, if the product is stored in the valve-up position for extended periods then it may be possible for the suspension to slowly leak back into the bulk suspension via the capillary channel. Loss of suspension from the metering chamber can subsequently result in a dose below nominal being dispensed after extended periods of non-use. The effect is not seen when the product is stored in valve-down orientation since there are no gravitational forces driving a loss of suspension from the metering chamber via the capillary. This effect is common to all MDI retention valves currently used in marketed products. In the case of Pulmicort HFA pMDI, it was found that this effect is only significant for storage periods of greater than 24 hours without use.

Pharmaceutical Assessor’s Comment (March 2008) The explanation for the storage orientation problem may be accepted on provision of data showing comparable orientation effect on other products. The Applicant should demonstrate that the routine storage in the valve-down position by the patient is practical and robust. This may be by the means of some user testing and clear instructions in the SPC, Patient Information Leaflet and product labelling. Samples of the product are requested below to ensure that the product will be physically stable if stored in this orientation.


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At a subsequent meeting of the CHM the company addressed this point

Company Response provided May 2008

As described in our previous response in March 2007, there is a gradual loss of suspension from the metering valve when the product is stored valve-up. This is a common characteristic for products using retention valves. Actual data for competitor products are not available but Package Insert texts for products registered in the USA include instructions to store with the mouthpiece down. Examples are Ventoline HFA pMDI and Flovent HFA pMDI. The following instructions relating to the storage orientation of the inhaler have been added to the SPCs, Patient Information Leaflet, carton and canister label: SPC: Store with the valve downwards after first use. PIL: Store your inhaler so that it stands upright on its brown plastic base (with the valve downwards). Carton: ↑ Store this way up Canister label: ↑ Store this way up To ensure that the routine storage in the valve-down position by the patient is practical and robust, a Focused User Test of the information on storage orientation in the PIL was conducted. Twenty participants were interviewed individually and asked to find, and express in their own words, the guidance on how to stand the inhaler when it is not being used. They were then given the inhaler and asked to demonstrate this guidance. All 20 participants successfully found and understood the information in the PIL and positioned the inhaler correctly. This demonstrates that the guidance in the PIL on storage orientation is legible and clear. Samples of the product have been provided together with this response. Pharmaceutical Assessor’s Comment (June 2008)

The Applicant’s response is considered reasonable It should be considered that the product is used in a preventative manner and would be used regularly (i.e. daily). The samples provided show that the product is physically stable when stored in the recommended position i.e. the product can stand upright on a flat surface in the valve down position. The Applicant has also suggested some clear labelling to ensure storage in this position by the patient. This point is considered resolved.


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2 The dose uniformity test method which is not in line with the Ph. Eur. Requirements is also considered a major point as all subsequent batch data and stability data have been generated with this test. There seems to be some intrinsic issue with dose uniformity as seen by some out of specification dose uniformity points observed in the stability data.

At the first meeting of the CHM the company presented data which partially resolved this issue. Subsequently, changes were made to the finished product specification and an updated test method was presented and this was considered a satisfactory resolution.

This point and all other pharmaceutical points were resolved.


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Main Clinical Points (March 2006) 1. There is inadequate evidence of safety in adults, adolescents and children as it is not

possible to confirm that budesonide formulated in an excipient mix including the non-chlorofluorocarbon propellant/the hydrofluoroalkane propellant, propellant HFA-134a, is not superior to or more potent than the original CFC-containing formulation of budesonide, and hence there are concerns regarding greater systemic exposure. Therefore further information on the comparison of these new formulations of budesonide with the original products in respect of systemic safety is required, particularly for use in children and at the top of the recommended dose range. Company Response provided Oct 2006, March 2007, Nov 2007 AstraZeneca are of the opinion that there was sufficient evidence to support the safety of budesonide formulated in an excipient mix including the non-chlorofluorocarbon propellant, the hydrofluoroalkane propellant, propellant HFA 134a, within the original data package submitted in June 2005 to resolve the issues raised in Clinical Point 1 and support the approval of these products. The Applicant has reviewed the data presented in the original submission which included one pharmacokinetic study (Study SKYE 2021-01), one 4-week pharmacodynamic study (Study SKY2021-004) and two 12-week clinical efficacy and safety studies (Studies SKY2021-002 and SKY2021-003) and considers that there is sufficient evidence to support the systemic safety of budesonide formulated propellant with HFA 134a to justify approval based on the following:

Systemic safety depends on total systemic exposure, and Study SKYE 2021-01 was internally consistent in that the pharmacokinetic evaluation showed either no or only a minimal difference in systemic plasma budesonide concentrations and the pharmacodynamic evaluation showed no difference in systemic effect between the HFA and CFC pMDIs (budesonide formulated with propellant HFA 134a and budesonide formulated with CFC propellants, respectively and administered via pressurised metered dose inhalers).

The discrepancy between the results for systemic effect between

SKYE 2021- 01 and SKY2021-004 is more than likely due to methodological issues in the latter.

In the original clinical assessment of the first two studies listed the following comments were made and conclusions drawn: The first of the two studies compared the single dose pharmacokinetics of budesonide in the two different formulations, CFC-free and CFC-containing, and evaluated dose proportionality. Although generally slightly higher systemic levels of budesonide were seen following budesonide formulated with propellant HFA 134a the 90% confidence intervals for the ratios of both area under the curve (AUC) and maximum plasma concentration (Cmax) fell within the pre-defined limits of 0.70-1.43 (and within the tighter limits of 0.80-1.25) and the two formulations were


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deemed to be bioequivalent. Dose proportionality was apparent for both formulations over the dosing range of 400-1600µg.

In this study the estimated ratios for plasma cortisol levels, test/reference, were close to unity, but when the arrythmetic means and the geometric means were reviewed plasma cortisol levels appeared to be lower following budesonide formulated with HFA 134a and administered in the highest dose of 1600µg than following budesonide formulated with CFC propellants and administered at the same dose.

Both the pharmacokinetic study and the pharmacodynamic study assessed systemic safety through the effects of budesonide on the hypothalamic pituitary adrenocortical (HPA) axis by measurement of plasma cortisol in the first study and through 12-hour overnight urine collections and measurement of urinary cortiosl/creatinine ratio in the second study. In both of these studies in healthy volunteers there was a suggestion of a slightly enhanced systemic effect with budesonide formulated with propellant HFA 134a with lower plasma cortisol levels seen following the administration of 1600µg in the first study, as described above, and a greater fall in urinary cortiosl/creatinine ratio over 4 weeks treatment with a dose of 800µg twice daily in the second study. In this second study this difference between the two formulations was statistically significant when all data were included in the analysis although the removal of one subject from the budesonide CFC treatment group in whom the data collected were described as extremely variable, did reduce this statistically significance between treatments to a non-significant difference. Numerically lower overnight urinary cortiosl levels were seen in the budesonide HFA treatment group compared with the budesonide CFC treatment group. The clinical significance of these findings was difficult to assess and it was deemed that further review alongside the findings in respect of systemic exposure in the pivotal efficacy studies was required. Unfortunately there were insufficient additional safety data in respect of systemic safety collected in the two Phase III safety and efficacy studies to alleviate the concerns.]

Reference to the considerable evidence for the systemic safety of Pulmicort

Turbohaler provides a margin of safety, since the difference in systemic exposure to budesonide between Pulmicort Turbohaler and Pulmicort CFC pMDI is larger than the difference between the HFA and CFC pMDI

The Applicant now attributes the differences seen between treatments in both the pharmacokinetic study (Study SKYE 2021-01) and the pharmacodynamic study (Study SKY2021-004) to the collection of variable data. In the pharmacokinetic study the lower mean plasma cortisol levels seen following budesonide formulated with HFA 134a and administered in a dose of 1600µg when compared with budesonide formulated with CFC propellants at the same dose, are attributed to the highly variable data collected in the budesonide CFC 1600µg treatment group where unusually high cortisol levels were measured in three subjects when treated at that dose level. The removal of


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these three subjects from the analysis removes the difference seen between the two treatment groups in respect of the fall in the mean values for plasma cortisol. Similarly and as commented on in the original assessment, the statistically significant difference seen in the pharmacodynamic safety study is explained by the Applicant as being attributable to one subject with highly variable data. The Applicant also states that in the measurement of the pharmacodynamic parameters in this second study there is added variability to the measurements due to factors such as variation in cortisol response to drug between and within individuals, sample collection methodology, assay performance, etc. Thus the discrepancy between the results of these two clinical studies is more than likely due to methodology issues. The Applicant makes reference to the extensive safety database generated following the administration of budesonide as Pulmicort Turbohaler and which the Applicant is of the opinion provides a significant safety margin for this new CFC-free formulation of budesonide administered via the pMDI. The Applicant bases the conclusions drawn on the following:

The systemic safety of budesonide is related to systemic exposure, regardless of what device is used, and thus pharmacokinetic data on systemic exposure are relevant for comparisons between devices.

The difference in systemic exposure to budesonide between Pulmicort Turbohaler and Pulmicort CFC pMDI (approximately 30%) is larger than the difference between the Pulmicort HFA and Pulmicort CFC pMDI (approximately 10%). Thus, the data strongly indicate that the systemic exposure is higher for Pulmicort Turbohaler than for Pulmicort HFA pMDI at the same dose.

While it has been shown that lung deposition and systemic exposure to budesonide are higher with Pulmicort Turbohaler than the current CFC pMDI device, the approved maximum dose for Pulmicort Turbohaler and Pulmicort pMDI is the same for both adults and children (1600 and 800µg/day respectively).

There are a considerable number of specific safety studies with Pulmicort Turbohaler that show no or minimal effects on the HPA axis at a dose of 1600µg/day in adults or 800µg/day in children, ie, the maximum recommended doses.

Thus, although the available data do not exclude a higher systemic exposure for Pulmicort HFA pMDI than for Pulmicort CFC pMDI, the systemic exposure to budesonide with Pulmicort HFA-pMDI is likely to be considerably less than that with Pulmicort Turbohaler, which would result in a significant margin of safety. Since the exposure from Pulmicort Turbohaler is as much as 50% greater than for a similar dose of Pulmicort CFC pMDI there is a considerable assurance of the robustness of this conclusion.


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The Applicant also refers to four published reports on the systemic effects of Pulmicort Turbohaler. Further to the Applicant’s initial response to Clinical Point 1 of the CHM Letter dated 6th July 2006 which comprised the review of the studies submitted with the original application and the reference to and review of data generated with Pulmicort Turbohaler, the Applicant has subsequently submitted a further pharmacodynamic/pharmacokinetic study: Study Code: D5252C00006 An open-label, randomised crossover study of budesonide pharmacokinetics and the effect of budesonide on 24-hour plasma/urine cortisol concentrations when administered via HFA pMDI, CFC pMDI and Turbuhaler for 6.5 days in healthy volunteers. (n=30) This open-label, randomised, 3-way crossover study was set up with the primary objective to compare the systemic effects of budesonide HFA pMDI with Pulmicort CFC pMDI through measurement of 24-hour plasma cortisol concentrations. Secondary objectives included:

Comparison of the systemic effects of budesonide HFA pMDI with Pulmicort CFC pMDI through measurement of 24-hour urinary cortisol concentrations.

Comparison of the systemic effects of budesonide HFA pMDI with Pulmicort Turbuhaler through measurement of 24-hour plasma/urinary cortisol concentrations.

To establish pharmacokinetic parameters for budesonide HFA pMDI, Pulmicort CFC pMDI and Pulmicort Turbuhaler at steady state.

Comparison of the pharmacokinetic parameters for budesonide HFA pMDI with Pulmicort CFC pMDI and with Pulmicort Turbuhaler following administration of a single dose with a charcoal block.

To assess safety through reporting of adverse events. The three formulations of budesonide administered in a strength of 200µg per actuation were administered in a dose of 4 actuations (800µg) twice daily for 6.5 days. On Day 1 of each treatment period subjects received the first dose of study treatment in the morning together with activated charcoal to block oral absorption. Plasma budesonide was measured over 12 hours post-dosing. On Day 6 subjects were admitted to the Clinical Pharmacology Unit prior to administration of the evening dose of study treatments which was followed by 2-hourly blood sampling for plasma cortisol measurements and a 24-hour urine collection. Following the morning dose of study treatments on Day 7


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plasma budesonide was measured over 12 hours post-dose. Each treatment period was separated from the next by a washout of between 12 and 30 days.

Fifty healthy volunteers at least 18 years of age were screened for entry to the study, 28 were randomised to treatment and 26 completed the study. Two subjects discontinued the study between treatment periods 2 and 3, one due to an adverse event and one due to withdrawal of consent. All 28 randomised subjects completed at least two treatment periods and therefore were included in the comparative analysis and all 28 randomised subjects were included in the safety analysis.

Pharmacodynamic Findings

AUC of plasma cortisol from 24-hour sampling at steady state, ratios of treatment effects (geometric means) from an ANOVA model in logarithmic scale – PD/PK data set 95% confidence interval

Ratio Estimate Lower Upper p-value

Budesonide HFA pMDI / Pulmicort CFC pMDI 1.018 0.934 1.110 0.6736

Budesonide HFA pMDI / Pulmicort Turbuhaler 1.373 1.258 1.499 <0.0001

Pulmicort CFC pMDI / Pulmicort Turbuhaler 1.349 1.237 1.470 <0.0001 AstraZeneca D5252C0000614AUG07:15:58:30 /Q-26389 Table 03.sas/Q-26389 Table 03.rtf

These findings suggest no statistically significant difference between budesonide HFA pMDI and Pulmicort CFC pMDI in respect of plasma cortisol AUC. However the findings in respect of the comparisons of the two formulations administered via the pressurised metered dose inhaler with Pulmicort Turbuhaler indicates that both formulations of budesonide administered via the pMDI had significantly less effect on plasma cortisol than budesonide when administered as Pulmicort Turbuhaler. The findings in respect of the 24-hour urinary cortisol, with and without correction for creatinine, were similar.


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Pharmacokinetic Findings

AUC0-12h and Cmax of budesonide at steady state, ratios of treatment effects (geometric means) from an ANOVA model in logarithmic scale – PD/PK data set

90% confidence interval

Parameter Ratio Estimate lower upper

p-value AUC0-12h Budesonide HFA pMDI /

Pulmicort CFC pMDI 1.030 0.900 1.178 0.7188

Budesonide HFA pMDI / Pulmicort Turbuhaler

0.512 0.446 0.587 <0.0001

Pulmicort CFC pMDI / Pulmicort Turbuhaler

0.497 0.435 0.569 <0.0001

Cmax Budesonide HFA pMDI / Pulmicort CFC pMDI

0.894 0.767 1.043 0.2287

Budesonide HFA pMDI / Pulmicort Turbuhaler

0.363 0.310 0.424 <0.0001

Pulmicort CFC pMDI / Pulmicort Turbuhaler

0.406 0.348 0.473 <0.0001

AstraZeneca D5252C0000604OCT07:16:01:17/Q-26389 Table 16-17.sas/Q-26389 Table 16-17.doc

The pharmacokinetic findings were consistent with the pharmacodynamic findings demonstrating that the systemic effects of budesonide HFA pMDI and Pulmicort CFC pMDI at steady state do not appear to differ based on plasma concentrations of budesonide – the mean treatment ratio between the two formulations of budesonide for AUC was close to 1.0 with 90% confidence intervals falling within the established limits for bioequivalence of 0.80-1.25. Consistency was also seen with the pharmacodynamic findings in respect of the comparisons of the two formulations administered via pressurised metered dose inhalers with Pulmicort Turbuhaler, with significantly lower plasma budesonide concentrations following inhalation from the pMDIs than from the Turbuhaler. Budesonide exposure following administration via the Turbuhaler appeared to be approximately twice that following inhalation via the pMDIs. The analyses of Cmax data were consistent with those of the AUC data. The systemic exposure to budesonide after single dose administration with a charcoal block differed between the three study treatments. Treatment ratios for AUC0-inf were 0.595 (p<0.0001) for budesonide HFA pMDI vs Pulmicort CFC pMDI, 0.413 (p<0.0001) for budesonide HFA pMDI vs Pulmicort Turbuhaler and 0.695 (p<0.0001) for Pulmicort CFC pMDI vs PulmicortTurbuhaler. Similar treatment ratios were estimated for Cmax.


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Safety Findings through Adverse Events

All three study treatments appeared to be safe and were well tolerated generally; no safety concerns were raised during the study. There were no deaths, serious adverse events or other significant adverse events during the study. With the exception of two severe adverse events (fainting) all events were described as mild or moderate in severity. One subject discontinued the study due to an adverse event (cervicitis) that was not considered to be causally related to study treatment by the investigator. The most common adverse events deemed to be causally related to study treatments were dysphonia (4 events), nausea (4 events), headache (3 events) and dry mouth (3 events). Applicant’s conclusions In conclusion the Applicant states that the systemic effects of budesonide HFA pMDI and Pulmicort (budesonide) CFC pMDI are comparable based on the evaluation of plasma cortisol, urinary cortisol and plasma budesonide concentrations following administration of study treatments for one week. When compared with budesonide administered via the Turbuhaler, budesonide administered via the pMDI appears to have a significantly lesser effect of on the HPA axis and to have significantly less systemic exposure at steady state – approximately half the systemic exposure seen following budesonide administered via the Turbuhaler. The Applicant makes no comment in the response document on the findings in respect of the systemic exposure to budesonide after single dose administration with a charcoal block and does not attempt to explain why exposure to budesonide HFA pMDI and Pulmicort (budesonide) CFC pMDI appears to be different under these conditions, although this was discussed in the Clinical Study Report. Children and Adolescents Clinical Point 1 of the CHM Letter dated 6 July 2006 also refers to inadequate evidence of safety in adolescents and children and concerns regarding greater systemic exposure and requests further information on the comparison of these new formulations of budesonide with the original products in respect of systemic safety not only at the top of the recommended dose range in adults but also in children. The Applicant has chosen to review the literature in this regard and has not submitted further new clinical data. The Applicant comments that although there are no studies that directly compare the pharmacokinetics of budesonide administered as Pulmicort CFC pMDI with the pharmacokinetics of budesonide administered as Pulmicort Turbohaler in children, there are data available to suggest that the relative systemic exposure to budesonide would


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also be lower in children when budesonide is administered via the pMDI than when administered via the Turbohaler. However the majority of these data were obtained with the budesonide CFC administered via the pMDI and NebuChamber® spacing device. The Applicant comments as follows on studies in children:

• In 6 children (10 to 13 years of age) the systemic availability of budesonide delivered by pMDI (with spacer) was approximately 30% of nominal dose, which is the same as in adults (Pedersen et al 1987).

• The pharmacokinetics of budesonide pMDI with NebuChamber were studied in 10 adults and 16 children from 2 to 6 years of age (Anhoj et al 2000). Budesonide pMDI with NebuChamber was found to deliver the same dose of budesonide to young children and adults and systemic exposure to budesonide was comparable between the two age groups.

• Comparison of results between two separate studies in adults and

children indicated that the systemic exposure of inhaled budesonide (AUC) delivered by the Turbohaler device is similar in school age children (800 µg) (Agertoft and Pedersen 2002) and adults (1000 µg) (Thorsson et al 2001).

• Furthermore, a crossover study in 15 asthma patients (5 to 15 years of

age) that compared the effects of budesonide by either pMDI with spacer or Turbohaler on 24-hour urinary cortisol excretion indicated that the systemic effects with the pMDI were measurably lower than with Turbohaler (Goldberg et al 2002).

The Applicant concludes that the data generated in these studies indicate that systemic exposure to budesonide is similar in children and adults whether administered via the pMDI with spacing device or the Turbohaler. Therefore systemic exposure to budesonide following administration as budesonide HFA pMDI or as budesonide CFC pMDI in children can be expected to be lower than that seen with Pulmicort Turbohaler, findings similar to those observed in adults. The Applicant has also reviewed 33 reports of adrenal crisis in the UK (Todd et al 2002), 28 cases in children and five in adults, and of theses 33 reports, 31 reports came from patients inhaling fluticasone propionate, two from patients inhaling beclometasone dipropionate and one from a patient inhaling both budesonide and fluticasone propionate. [The Applicant comments that at the time of the Todd Report fluticasone propionate had the smallest prescription share.]

In conclusion, the Applicant states that in their opinion there is sufficient evidence to support the systemic safety of budesonide formulated in an


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excipient mix including the non-chlorofluorocarbon propellant/the hydrofluoroalkane propellant, propellant HFA 134a, and hence support approval for use in the management of asthma in both adults and children. However to enhance the safety of these new formulations the Applicant makes the following proposals:

• Addition of a precaution that when patients are transferred to Pulmicort HFA pMDI from other devices, the dose should be adjusted according to the clinical response. As previously, the dose should be adjusted to the minimum required to maintain good asthma control.

• A lower age limit of 2 years for Pulmicort HFA pMDI (in accordance

with the request of the MHRA to specify age limits for dosing in children), and maximum doses of 400µg daily for children aged 2 to 7 years, 800µg/day for children 7 to 12 years, and 1600µg/day for children above 12 years and adults (as compared with 800µg daily for children of all ages for Pulmicort CFC pMDI). The upper age limit, 12 years is the same as for Pulmicort Turbohaler.

Statistical Assessor’s Comment (March 2006)

The concerns with the studies submitted in the original applications remain. However, the newly submitted PK/PD study does provide convincing evidence that the safety of budesonide HFA pMDI is equivalent to that of Pulmicort CFC pMDI. In terms of PK, the 90% confidence interval for AUC0-12h is (0.9,1.18) and the ratio of Cmax between budesonide HFA pMDI and Pulmicort CFC pMDI is 0.89 with a 90% confidence interval of (0.77,1.04). Taking the AUC and Cmax results together suggests that the systemic safety of the budesonide HFA pMDI is comparable with Pulmicort CFC pMDI. This is confirmed by the plasma cortisol PD data where the 95% confidence interval for the ratio of AUC plasma cortisol is (0.93,1.1). However, the results using the charcoal block are very surprising and cast doubt over the efficacy of budesonide formulated with HFA 134a. These results are presented in the tables below: (Note to reader: Both the Company and the assessor understood that the charcoal block data presented below do not reflect the steady state results in the study, due to issues with the clinical trial supplies, and therefore may give an inconsistent view of the results for budesonide with HFA 134a. Please refer to page 62-65 for the final resolution on this issue.)


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There are clear differences between the AUC and Cmax for the 3 formulations. The results from a single dose administration combined with an activated charcoal block should reflect the amount of active drug absorbed into the systemic circulation from the lungs and may be viewed as a surrogate measure


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of efficacy. Therefore, these findings may cast serious doubts over the claim that budesonide HFA pMDI is non-inferior to Pulmicort CFC pMDI. The Applicant provides the following discussion of this issue in the Study Report:

However, an unexpected finding was that the ratio between HFA and CFC following a single dose with charcoal was 0.595, suggesting that the delivery of budesonide to the lung with the CFC product is higher than with the HFA. Further examination of the single dose with charcoal data for the CFC pMDI suggests that these data are unusual. A comparison of AUC0-12h for single dose versus steady state with CFC pMDI indicates that the values were nearly the same. This is inconsistent with the fact that charcoal has been demonstrated to block approximately 40% of the systemic concentration of budesonide from CFC pMDI (Thorsson et al 1994) and that there is expected to be about a 30% increase in plasma budesonide concentrations from single dose to steady-state (Kaiser et al 1999). In the HFA pMDI and Turbuhaler treatments there was an expected increase in AUC0-12h

from the single dose to steady-state. Likewise, a comparison between the present study and the single dose (without charcoal) PK study that was conducted earlier (AstraZeneca Clinical Study Report D5252C00001 /SKYE2021-01, 2003) indicates that AUC0-12h for the CFC treatment in the present study was actually slightly higher compared to that when administered without charcoal in the previous study. For the HFA treatment, the AUC0-12h in this study was reduced to an expected degree versus the previous PK study without charcoal (AstraZeneca ClinicalStudy Report D5252C00001 /SKYE2021-01, 2003). The reason for the unexpectedly high exposure during the single dose with charcoal treatment with CFC pMDI is not currently known, however, these results do not affect the interpretation of the primary objective of this study, or the other secondary objectives.

The Applicant has provided evidence that the levels measured were unusual. However, a sufficient argument to ignore the differences seen between formulations has not been provided. As the plasma levels of budesonide reaching the lungs are considerably lower for budesonide HFA pMDI than for Pulmicort CFC pMDI serious doubts over efficacy are now raised such that therapeutic equivalence may be deemed to be not established.

The previously submitted clinical studies do not allay these fears. In the clinical studies presented only one dose of budesonide was tested for each severity of asthma studied. Therefore, if the current stance adopted in the Draft CHMP Guideline on the Requirements for Clinical Documentation for Orally Inhaled Products (OIP) including the Requirements for Demonstration of Therapeutic Equivalence between Two Inhaled Products for Use in the Treatment of Asthma and Chronic Obstructive Pulmonary Disease (COPD) is accepted, the assay sensitivity of these studies has to be questioned.

In light of the new results presented the safety of the budesonide HFA pMDI

is considered to have been satisfactorily demonstrated. However the results UKPAR AstraZeneca UK Ltd, Pulmicort CFC-free Inhalers 100 and 200 micrograms

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following the use of activated charcoal raise questions over the efficacy of budesonide HFA pMDI which is now considered to be a new unresolved issue. Ideally the Applicant should repeat this part of the study to provide reassurance that these are rogue findings.

Clinical Assessor’s Comment (August 2008)

The new pharmacodynamic/pharmacokinetic study submitted as part of the response to Clinical Point 1 of the CHM Letter dated 6 July 2008 provides more definitive data in respect of the systemic effects and systemic safety of budesonide formulated in an excipient mix including the non-chlorofluorocarbon propellant, propellant HFA 134a, than in the original submission. The study is more robust in its design and choice of endpoints than the earlier studies, with measurement of plasma cortisol and urinary cortisol over 24 hours at steady state (with overnight stay in the investigation unit), measurement of plasma budesonide at the same time points as plasma cortisol, and a more rigorous assessment of compliance with dosing of study treatments. The design of the study with the three endpoints described above provided internal consistency and assay sensitivity was demonstrated through statistically significant changes from baseline plasma cortisol seen with all three study treatments. The demonstration of significantly greater effects on both plasma and urinary cortisol following inhalation of budesonide as Pulmicort Turbuhaler when compared with the effects on these parameters seen following inhalation of budesonide as either budesonide HFA pMDI or budesonide as Pulmicort CFC pMDI, findings which were consistent with increased plasma budesonide concentrations seen in the Turbuhaler treatment group, further confirmed assay sensitivity of this study. The finding in this study confirm that the systemic effects and the systemic safety of budesonide formulated with HFA 134a (budesonide HFA pMDI) and budesonide formulated with CFC propellants (Pulmicort CFC pMDI) are comparable based on the evaluation of plasma cortisol, urinary cortisol (both uncorrected and corrected for creatinine) and plasma budesonide concentrations following administration of the two formulations of budesonide for seven days.

When compared with budesonide administered via the Turbuhaler, budesonide administered via the pMDI appears to have a significantly lesser effect of on the HPA axis and to have significantly less systemic exposure at steady state – approximately half the systemic exposure seen following budesonide administered via the Turbuhaler. However the Applicant makes no comment in the response document on the findings in respect of the systemic exposure to budesonide after single dose administration with a charcoal block and does not attempt to explain why exposure to budesonide HFA pMDI and Pulmicort (budesonide) CFC pMDI appears to be different under these conditions, although this was discussed within the Clinical Study Report. It would appear that both budesonide HFA


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pMDI and Pulmicort CFC pMDI provide a statistically significantly lesser systemic load than Pulmicort Turbuhaler but that budesonide HFA pMDI also provides a statistically significantly lesser systemic load than Pulmicort CFC pMDI. In the absence of any clinical efficacy studies these findings might raise questions over the comparative efficacy of the two formulations of budesonide administered via pressurised metered dose inhalers, budesonide HFA pMDI and Pulmicort (budesonide) CFC pMDI, and suggest that the HFA formulation might be inferior to the CFC formulation. One clinical efficacy study in adults was submitted with the original applications for Marketing Authorisations for these CFC-free pressurised metered dose inhalers in August 2005. This study did assess two doses of budesonide formulated with propellant HFA 134a but one dose, the lower dose of 400µg per day was administered to a milder group of patients with asthma (FEV1 % predicted 81% to 90%) and the other dose, the higher dose of 800µg per day was administered to a more severe group (FEV1 % predicted 50% to 80%); the study assessed different severities of disease but only assessed one dose of budesonide in each severity of disease such that no assessment of a dose-response effect could be made. Therefore the study should have been deemed to have lacked sufficient assay sensitivity to draw any conclusions in respect of therapeutic equivalence or non-inferiority. However at the time of the original assessment of this study, the study design with an active control and a run-in period during which patients’ eligibility for entry to the study was assessed – all patients entered all had a baseline level of asthma symptoms, a need for rescue inhaled bronchodilator therapy and less than optimal pulmonary function such that a population of patients with asthma and with room for improvement in asthma control would be studied and therefore if there were clinically important differences between study treatments in respect of efficacy these entry criteria would provide an increased likelihood of these differences being detected – was deemed appropriate, enhancing sufficiently the sensitivity of the study. The conclusion drawn following assessment was one of non-inferiority of budesonide when formulated with propellant HFA 134a and compared with budesonide formulated with CFC propellants. The second pivotal efficacy study submitted with the original applications was an almost identical study but carried out in children aged between 6 and 12 years. This study only assessed one dose of budesonide and therefore may also be deemed to have lacked sufficient assay sensitivity to draw any conclusions in respect of therapeutic equivalence or non-inferiority. Therefore the re-appraisal of the original studies, both the study in adults and the study in children, taken together with the findings in the more recently completed pharmacodynamic/pharmacokinetic study, Study D5252C00006 in respect of the suggestion that the HFA formulation of budesonide might be inferior to the CFC formulation raise serious concerns over the efficacy of this


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new CFC-free formulation. It is considered that the Applicant should carry out a further comparison of the pharmacokinetic parameters for budesonide formulated with HFA 134a with those of budesonide formulated with CFC propellants (Pulmicort CFC pMDI) and Pulmicort Turbuhaler following administration of a single dose with a charcoal block to provide reassurance that the conclusions of non-inferiority drawn in the original clinical studies can still stand. The concerns now raised in respect of the efficacy of this new formulation of budesonide are new and will require resolution prior to the grant of any Marketing Authorisations.

The Applicant’s further review of the pharmacokinetic and pharmacodynamic data presented in the original submission, with exclusion from the analyses of data described as highly variable, is not accepted and does not change the conclusions drawn following the original assessment of these studies. The review of the original data contributes nothing to the final conclusions now drawn in respect of the safety of these new formulations of budesonide.

The Applicant has chosen not to carry out a clinical safety study with budesonide formulated with propellant HFA 134a in children but has reviewed the literature in respect of the use of budesonide formulated with CFC propellants and formulated as a dry powder administered via the Turbohaler. The CPMP Note for Guidance: Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products III/5378/93 – Final does state that these re-formulated pressurised metered dose inhalers should be developed not only for use in adults but also for use in children. In the original submission the Applicant did present a 12-week pivotal efficacy study in children aged 6 to 12 years but this study did not assess systemic effects of this inhaled corticosteroid. Although it has been requested that the systemic safety of these re-formulated inhalers should be studied in children, in the light of the findings in respect of systemic effects and systemic safety in the pharmacodynamic/ pharmacokinetic safety study presented, and described at 5.1.1 above, in adults, Study D5252C00006, and in the light of the fact that a 12-week study has been carried out in children aged 6 to 12 years in which 77 children received treatment with budesonide formulated with propellant HFA 134a, and in which budesonide appeared well tolerated and in which no unusual or unexpected adverse events were reported, it is considered appropriate to propose that Marketing Authorisations should be granted for use of these new products in children without the need for a further clinical safety study in this young age group. However such Authorisations can only be granted subject to satisfactory resolution of the new concerns now raised in respect of the efficacy of this new formulation of budesonide.

However in the light of no specific clinical safety data available in children following the inhalation of budesonide formulated with the non-CFC propellant, propellant HFA 134a, the Commission is asked to comment specifically on this decision.


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Point 1 may be considered resolved in respect of the systemic safety of these new products in adults, adolescents and children. However the concerns raised in respect of the efficacy of this new formulation of budesonide are new and will require resolution prior to the grant of any Marketing Authorisations. Please see Page 61 for the resolution of this major new issue.

2. The difference between the dose and regimen as stated for these CFC-free inhalers

when compared with the original CFC-containing products at the lower limit of the dose range for use in children is not acceptable. The dose and dose regimens must be identical to the dose and dose regimens of the original products unless the change to the lower limit of the dose range can be justified clinically.

Company response provided Feb 2007 The Applicant believes that there is sufficient clinical justification for a change in the minimum dose recommended for use in children from 50 micrograms twice daily to 100 micrograms twice daily. The Applicant discusses again the very limited data presented with the submission for the original CFC-containing products (granted Marketing Authorisations in 1982) in respect of the minimum dose recommendations for children – only one out of nine clinical studies carried out assessed the efficacy of budesonide when administered in a dose of 100 micrograms per day and the Applicant claimed that Limited efficacy was seen at the 100 microgram dose, and taking into account the limited sample size (n=19), it was concluded that 100 microgram/day was a subtherapeutic dose. Thus, the lowest currently recommended dose in the UK, 100 microgram/day is supported by limited clinical data. In this study there was no placebo and it was difficult to determine what the treatment effect was, if any, at a dose of 50 micrograms twice daily and therefore not possible to know whether some children might derive benefit from this very low dose regimen or not. The Applicant suggests that the proposed higher new minimum dose recommendation for use in children is based on all currently available data and including data generated in children treated with Pulmicort Turbohaler and also improves the consistency of dosing recommendations across all formulations of budesonide. The Applicant reviews the literature in respect of the safety of a minimum dose of 200 micrograms daily and looks at benefit-risk considerations. The following table gives the dose recommendations for children for all formulations of budesonide, as Pulmicort, in the UK:


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Summary of approved doses of budesonide (all formulations) and proposed dose of Pulmicort HFA pMDI Current Proposed Pulmicort Respules Children 3 months to 12 years Initial dose 0.5-1 mg twice daily Maintenance dose 0.25-0.5 mg twice daily Pulmicort Turbohaler Children 12 years of age and under 200 to 800µg daily in divided doses. During periods of severe asthma the daily dose can be increased up to 800µg. Once daily dosing: 200µg to 400µg may be used in children with mild to moderate asthma who have not previously received inhaled glucocorticosteroids or who are already well controlled [on inhaled glucocorticosteroids] Pulmicort pMDI (CFC) Children 50 to 400µg twice daily. During periods of severe asthma the daily dose can be increased up to 800µg

NA NA Pulmicort pMDI (HFA) Children 7 -12 years 200-800µg daily, divided into 2-4 administrations. Children 2-7 years 200-400µg daily, divided into 2-4 administrations.

The Applicant states that in most countries (worldwide) the lower limit of the dose range for Pulmicort Inhaler CFC-containing for use in children is 200 micrograms per day and in the majority of European countries the lowest approved dose regimen for use in children is also 200 micrograms as a total daily dose. The exceptions to this are the UK, Denmark and Ireland where the lowest approved maintenance dose for use in children is 100 micrograms per day and Belgium with a lowest approved dose regimen of 50 micrograms per day. The Applicant concludes that there is no indication of any negative safety implications for children when the lowest recommended dose of budesonide, when formulated with propellant HFA 134a, is increased from 50 micrograms twice daily to 100 micrograms twice daily. However it is proposed that to ensure the safety of this new formulation of budesonide when administered to children a lower age limit for use of 2 years should be imposed together with recommendations for a lower maximum total daily dose in the 2 to 7 year age group than in the 7 to 12 year age group as follows:


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• Children aged 2 to 7 years – a maximum total daily of 400 micrograms

• Children aged 7 years and above – a maximum total daily dose of

800 micrograms

The justification is accepted and this point is resolved.

3 The product literature should recommend a specific named spacing device for use

with this new formulation of budesonide administered as a pressurised inhalation suspension. A spacing device should always be available together with a pressurised metered dose inhaler when such is prescribed for use by a child.

Company Response provided Feb 2007

The Applicant agrees that a spacing device should be recommended for use with this CFC-free pressurised metered dose inhaler and that a spacing device should always be available together with a pMDI when such is prescribed for use by a child. The NebuChamber spacing device was used in the clinical study in children (Study SKY2021-003) presented in the original application and therefore this device will be available for Healthcare Professionals to prescribe and will be referenced in the product literature, including the Summaries of Product Characteristics, the Patient Information Leaflet and product labelling

Clinical Assessor’s Comment (March 2008)

The NebuChamber spacing device is an appropriate spacing device to be used with this new CFC-free formulation of budesonide administered via a pMDI. The device was used in a sub-population of children aged between 6 and 12 years recruited into a pivotal efficacy study – 78% of children in each treatment group (test and reference – the Applicant’s own CFC-containing formulation of budesonide - treatment groups) received the study treatments administered via a pMDI and NebuChamber spacing device. Similar efficacy was observed in both treatment groups, both in children who had and in children who had not used the device. There were no statistically significant differences in FEV1 (the primary endpoint) between the two treatment groups both for children who used the spacing device and for children who did not use the spacing device; in the measurement of PEFR (a secondary endpoint) there were no differences between treatment groups for children using the spacing device, however differences were seen between treatment groups for children not using the spacing device with a greater increase seen in the budesonide CFC-containing pMDI treatment group. It was considered that this difference was likely to be due to the smaller numbers of children not using the spacing device, only some 20% of the total study population, and hence the larger variation in response to treatment.

The findings from this study suggest that in a population of children who would normally use a spacing device with a pressurised metered dose inhaler


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there appears to be no difference between the two treatments (CFC-free and CFC-containing formulations of budesonide), and the overall conclusion drawn from this study, that budesonide formulated with propellant HFA 134a provides equivalent asthma control when compared with budesonide formulated with CFC propellants and when administered at the same dose, applies regardless of whether the product is delivered via a pressurised metered dose inhaler alone or via a pressurised metered dose inhaler with NebuChamber spacing device.

This point is resolved.

4 The non-inferiority margins in the two pivotal clinical efficacy studies were

somewhat wide and should be justified. Company Response provided Feb 2007

The Applicant’s written response is shown below:

We would like to draw the attention of the reviewer to Section 2.5.1.3 (page 10) of the Clinical Overview of the original CTD application, where discussions with regulatory agencies are reviewed, including discussion regarding choice of non-inferiority margins. Briefly, the MCA (now MHRA) recommended at the scientific advice meeting that took place on 10 March 2003 that literature data be provided to support the proposed value (in the adult study) of 20 L/min. Accordingly, the choice of non-inferiority margins (for both adults and children) is justified in Section 2.5.4 of the Clinical Overview (page 18) based on reference to a number of clinical studies. In retrospect, we acknowledge that 20 L/min may be seen as a fairly high value for a noninferiority margin in the adult study, and would be less controversial as a limit in a superiority study. However, further support for the non-inferiority of the HFA formulation is provided by an additional analysis in which we pooled the low-dose and high-dose groups together, thereby increasing the power of the comparison. In this analysis, the 95% confidence interval for the difference in morning PEFR between HFA and CFC was (-6.7, 13.3) with a point estimate of 3.3 L/min. This confidence interval falls entirely within ±15 L/min, a limit previously used as support for therapeutic equivalence (Bateman et al 2001). For the paediatric study, we also acknowledge that 10% is a fairly high value for a noninferiority margin. However, the results of the study show that a substantially smaller choice of non-inferiority margin would have yielded a conclusion of non-inferiority. The upper limit for the two-sided 95% confidence interval for the difference between HFA and CFC was 2.4% (<10%) in the per protocol analysis set, and the corresponding upper limit for the full analysis set was 1.8%.

Statistical Assessor’s Comment (March 2008)


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In light of the new doubts over the efficacy of budesonide formulated with propellant HFA 134a this point has added significance. It is accepted that in the literature similar margins have been used and considered to be acceptable. It is accepted that the actual confidence intervals lie well inside these limits and therefore this point can be considered resolved. However, given the new concerns over the efficacy of the budesonide HFA 134a formulation in the new PK/PD study using activated charcoal it should be noted that the choice of non-inferiority margin is not now the major issue with the clinical studies. The major issue now is that for each severity of asthma only 1 dose level of budesonide was studied and therefore the assay sensitivity of the study is questioned. In this situation the choice of limits is irrelevant if it is considered that say half or double the dose would have given a similar clinical change in lung function. At present the best measure of efficacy comes from the activated charcoal PK data which suggests that the HFA product is inferior to the CFC formulation.

This point may be considered resolved 5. Specific Adverse Events

Nasopharyngitis and headache do not feature in the SPCs for the CFC-containing pressurised metered dose inhalers or the dry powder formulations of budesonide and therefore in the light of the high incidence of these events seen in the studies presented consideration should be given to including these events within the SPC, Section 4.8 for both strengths of this new CFC-free pMDI (consideration should also be given to the inclusion of these adverse events in the SPCs for other formulations of budesonide). Response from the applicant in February 2007: “AZ do not see Nasopharyngitis or Headache as causally Drug related AEs. Both these conditions are common in the general population and frequently reported in different scenarios of clinical trials, although the rates may vary considerably. Regarding Nasopharyngitis in pooled Turbohaler studies, the incidence was 15.89% in the Pulmicort group vs 15.67% in the placebo group and 23.35 % in the CFC group. In studies with the new Pulmicort HFA pMDI (This application), the rate was lower both in the HFA group (11%) and CFC group (9%). Taken together we do not see any signal of a causal relationship between Nasopharyngitis and Pulmicort HFA. Regarding Headache in pooled Turbohaler studies, the incidence was 8.98% in the Pulmicort group vs 8.37% in the placebo group, and 23.95 % in the CFC group. In Skye Pharma studies, the rate was lower in the HFA group (6%) vs CFC (11%). Taken together we do not see any signal of a causal relationship between Headache and Pulmicort HFA.”

The Applicant’s arguments not to include the adverse events of nasopharyngitis and headache are accepted.

This point may be considered resolved


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6. Post_Markeing Surveilliance Study

The requirement to carry out a Phase IV safety study is described in The CPMP Note for Guidance: Replacement of Chlorofluorocarbons (CFCs) in Metered Dose Inhalation Products III/5378/93-Final. This CPMP Note for Guidance requests that applications for Marketing Authorisations for metered dose inhalation products containing propellant HFA 134a should include proposals to monitor the introduction of the new non-CFC products in order to identify rare and unexpected adverse events. A method such as the use of record linkage schemes should be considered as these could provide a means for prospectively monitoring new non-CFC propellants against historical data relating to the products using CFC propellants.

The company are proposing a Prescription Event Monitoring Study run by the Drug Safety Research Unit (DSRU) as the response to a request for an observational cohort study or blinded trial. A full definitive protocol for this Prescription Event Monitoring Study was submitted and agreed with the Vigilance and Risk Management of Medicines (VRMM) Division/Pharmacovigilance Risk Management Group, MHRA before commencement of the study. This point is resolved.


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Commission On Human Medicines – March 2008 The Applications were further considered by the Commission on Human Medicines at a Pre-Hearing held during their meeting on 14 March 2008.

The Commission considered that the data submitted in the written response in respect of the safety of these products raised new concerns in respect of the efficacy of these products and therefore had reason to think that on grounds now relating to efficacy that they may be unable to advise that the Marketing Authorisations applied for should be granted. All points raised by the Commission on the original applications and following the Pre-hearing are either resolved or are resolvable subject to conditions listed but with the exception of the concerns raised in respect of efficacy of this new formulation of budesonide (formulated in an excipient mix including the non-chlorofluorocarbon propellant/the hydrofluoroalkane propellant, propellant HFA 134a), a Major New Point raised following the Pre-hearing, on which it is recommended that the Applicant should be heard prior to the grant of any Marketing Authorisations. Further to the responses to points raised on these applications following the original assessment and based on the further evidence now presented to the Commission, the Commission are of the view that there are now new and serious concerns raised over the efficacy of this new formulation of budesonide, formulated in an excipient mix including the non-chlorofluorocarbon propellant/the hydrofluoroalkane propellant, propellant HFA 134a, and that this new formulation of budesonide might be inferior in respect of efficacy to the original budesonide formulated with CFC propellants.


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Commission on Human Medicine June 2008 The company response submitted 1 May 2008 to the major new point can be found below.


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The major new point can be considered resolved. Marketing Authorisations for the two products can be granted.


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OVERALL CONCLUSION AND RISK/BENEFIT ANALYSIS

Quality The important quality characteristics of Pulmicort® are well defined and controlled. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. Pre-Clinical No new preclinical data were submitted and none are required for applications of this type.

Clinical

The applicant has demonstrated that the Pulmicort® HFA Inhaler is non-inferior to the Pulmicort® CFC Inhaler. Any safety concerns arising from these applications have been fully resolved . The SPC, PIL and labelling are satisfactory.

Risk/Benefit Analysis The quality of the product is acceptable and no preclinical safety concerns were raised and any clinical safety concerns were fully resolved. The risk benefit is, therefore, considered to be positive.


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STEPS TAKEN DURING ASSESSMENT 1

The MHRA received the application on 17/08/2005.

2

Following standard checks and communication with the applicant the MHRA considered the application valid on 15/09/2005.

3

Following assessment of the application the MHRA the assessment reports were considered by the Chemistry, Pharmacy and Standards (CPS) subcommittee on 11/04/2006.

4

Following assessment of the application the MHRA the assessment reports were considered by the Commission on Human Medicines (CHM) 22/06/2006.

5

The applicant was informed that the CHM could not recommend the granting of market authorisations on 06/07/2006

6

The applicant appealed on 26/07/2006. The applicant provided further information 16/03/2007 in response to the CHM assessment.

7

At a pre-hearing the CHM considered the appeal data 14/03/2008.

8

The applicant was informed that the CHM could not recommend the granting of market authorisations on 19/03/2008

9

The applicant provided further information on 01/05/2008 addressing the points raised in the assessment dated 19/03/2008

10

The CHM considered the additional data at a pre-hearing meeting on 19/06/2008.

11

A letter dated 09/07/2008 stating the CHM considered that subject to changes in the SPC and PIL market authorisations may be granted. The applicant responded to these concerns 31/07/2008.

12

Further information was requested by the assessor on 02/09/2008. Applicant responded to the request by addressing the points on 05/09/2008. A further request for information was requested by the assessor on 10/09/2008. The applicant responded 12/09/2008. Market Authorisations were granted on 24/09/2008


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STEPS TAKEN AFTER ASSESSMENT No non-confidential changes have been made to the market authorisation.


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Pulmicort CFC-free Inhaler 200 micrograms. ▼

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose (ex-valve)/actuation contains budesonide 200 micrograms. For full list of excipients, see Section 6.1.

3 PHARMACEUTICAL FORM Pressurised inhalation, suspension. The NebuChamberTM spacer device is the only spacer device to be used with Pulmicort CFC-free Inhaler.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Asthma.

4.2 Posology and method of administration For inhalation use. Adults, including the elderly: 200 micrograms twice daily, in the morning and in the evening. During periods of severe asthma the daily dosage can be increased up to 1600 micrograms. A lower strength inhaler (Pulmicort CFC-free Inhaler 100 micrograms) is available and should be used in patients whose asthma is deemed to be well-controlled and in whom the total daily dose may be reduced to less than 400 micrograms. The daily dose should not go below 200 micrograms. The dose should be reduced to the minimum needed to maintain good asthma control. Children 2-12 years: 200 to 800 micrograms daily in divided doses. A lower strength inhaler (100 microgram) is available for use in children with mild/moderately severe asthma. The dose should be reduced to the minimum needed to maintain good asthma control.


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Pulmicort CFC-free Inhaler is not recommended for use in children less than 2 years of age. Patients maintained on oral glucocorticosteroids Pulmicort CFC-free Inhaler may permit replacement or significant reduction in the dosage of oral glucocorticosteroids while maintaining asthma control. For further information on the withdrawal of oral corticosteroids see Section 4.4 (Special warnings and precautions for use). Method of Administration Instructions for the correct use of Pulmicort CFC-free Inhaler Note: It is important to instruct the patient to:

• Carefully read the detailed instructions for use and refer to the accompanying pictograms in the Patient Information Leaflet that is packed with each inhaler.

• Take his/her time when using the inhaler and not to rush through the individual steps.

• To practise using the inhaler in front of the mirror. Advise the patient that if any mist is seen coming from the top of the inhaler or from the mouthpiece it may mean that he/she has not inhaled the medicine properly.

• Shake the inhaler thoroughly for a few seconds to mix the contents of the inhaler properly.

• Prime the inhaler by actuating it twice into the air when the inhaler is new, if it has been dropped, or when it has not been used for more than 7 days.

• Place the mouthpiece in the mouth. While breathing in slowly and deeply, press the canister firmly to release the medication. Advise the patient that he/she may need to use both hands to operate the inhaler. Continue to breathe in and hold the breath for as long as is comfortable.

• Remove the inhaler from the mouth before breathing out; the patient must be advised that he/she must not breathe out through the inhaler.

• If a second or subsequent actuation is required the patient should be advised to wait for about half a minute and then replace the mouthpiece in the mouth and repeat the instructions at the preceding two bullet points, the sixth and seventh bullet points as listed.

• Rinse the mouth out with water after inhaling the prescribed dose to minimise the risk of oropharygeal thrush.

• Clean the mouthpiece of the inhaler regularly, at least once a week. Remove the dust cap and the aerosol canister. Clean the plastic actuator and dust cap with a dry cloth or tissue. Refer to the detailed instructions for cleaning in the Patient Information Leaflet, which is packed with each inhaler. Advise the patient that the metal aerosol canister should not be put into water or be cleaned with water.


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• Always store Pulmicort CFC-free Inhaler so that it stands upright on its brown plastic base (with the valve downwards).

The use of Pulmicort CFC-free Inhaler with the NebuChamberTM spacer device is recommended to enable patients with difficulty in co-ordinating inhalation with actuation, such as infants, young children, the poorly co-operative or the elderly, to derive greater therapeutic benefit. The mouthpiece of Pulmicort CFC-Free Inhaler fits directly into the NebuChamber spacer device. Pulmicort CFC-free Inhaler should only be used with the NebuChamber spacer device, it should NOT be used with any other spacer device as an alternative device may alter the pulmonary deposition of budesonide. A spacer device should always be available together with a pressurised metered dose inhaler when a pressurised metered dose inhaler is prescribed for use by a child. Instructions for the correct use of Pulmicort CFC-free Inhaler with the NebuChamberTM spacer device. Note: It is important to instruct the patient to:

• Carefully read the instructions for use in the Patient Information Leaflet, which is packed with each inhaler.

• Carefully read the instructions for use in the instruction leaflet, which is packed with each spacer device.

On actuation of the aerosol the dose is released into the inhalation chamber. The inhalation chamber is then emptied by two slow deep breaths. Young children may need to breathe 5–10 times through the mouthpiece. For further doses the procedure is repeated. It is important to explain that when a small child is using the NebuChamber spacer device a parent or carer should hold and support the spacer device in the child’s mouth to ensure that the child breathes through the spacer device properly. For young children who are unable to breathe through the mouthpiece, a face mask can be used. Compatible face masks are available separately and care should be taken to ensure a good fit is achieved.

4.3 Contraindications History of hypersensitivity to budesonide or any of the excipients. Active pulmonary tuberculosis. Special care is needed in patients with quiescent pulmonary tuberculosis and with fungal and viral infections in the airways.

4.4 Special warnings and precautions for use Patients not dependent on steroids: Treatment with the recommended doses of budesonide usually gives a therapeutic benefit within 7 days. However, certain patients may have an excessive collection of mucus secretion in the bronchi.


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In these cases, a short course of oral corticosteroids (usually 1 to 2 weeks) should be given in addition to the aerosol. After the course of the oral drug, the inhaler alone should be sufficient therapy. Steroid-dependent patients: Transfer of patients on oral steroids to treatment with Pulmicort CFC-free Inhaler demands special care, mainly due to the slow restitution of the disturbed hypothalamic-pituitary adrenocortical axis function, caused by extended treatment with oral corticosteroids. When the Pulmicort CFC-free Inhaler treatment is initiated the patient should be in a relatively stable phase. A high dose of budesonide, in combination with the previously used oral steroid dose, should be given for about 10 days. The down titration dose should be selected at the discretion of the physician, based on the patient’s disease and former steroid intake. For example, a down titration with 5 mg prednisolone per day, on a weekly basis; this reduction will mean that a daily dose of 20 mg per day would be reduced to 15 mg per day in the first week, 10 mg per day in the second week etc. The oral dose is thus reduced to the lowest level that, in combination with budesonide, provides maintained or improved asthma control. In many cases it may be possible to completely substitute the oral steroid with inhaled budesonide; however some patients may have to be maintained on a low dose of oral steroid together with inhaled budesonide. During the withdrawal of oral steroids some patients may experience uneasiness and may feel generally unwell in a non-specific way even though respiratory function is maintained or improved. Patients should be encouraged to continue with inhaled budesonide whilst withdrawing the oral steroid unless there are clinical signs to indicate the contrary. Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy and hence oral steroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances HPA axis function should be monitored regularly. These patients should be instructed to carry a steroid warning card indicating their needs. Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress such as severe infections or elective surgery. Such patients should be instructed to carry a steroid warning card indicating their needs (See also Section 4.8.Undesirable effects). Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs which might be seen in acute adrenal crisis may be somewhat vague but may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia. Treatment with supplementary systemic steroids or inhaled budesonide should not be stopped abruptly. During transfer from oral therapy to Pulmicort CFC-free Inhaler, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be


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suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary. Exacerbations of asthma caused by bacterial infections are usually controlled by appropriate antibiotic treatment and possibly increasing the budesonide dosage or, if necessary, by giving systemic steroids. 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 straightaway. Pulmicort CFC-free Inhaler should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids be regularly monitored. If growth is slowed therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist. Pulmicort CFC-free Inhaler is not intended for rapid relief of acute episodes of asthma or symptoms of asthma. In these situations an inhaled short-acting bronchodilator is required. Patients should be advised to have such ‘rescue’ medication with them at all times. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual and respiratory symptoms persist, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy e.g. higher doses of inhaled budesonide, the addition of a long-acting beta agonist or a course of oral glucocorticosteroids. Patients should be reminded of the importance of taking prophylactic therapy regularly, even when they are asymptomatic. Patients should also be reminded of the risk of oropharyngeal Candida infection, due to drug deposition in the oropharynx. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. Oropharyngeal Candida infection usually responds to topical anti-fungal treatment without the need to discontinue the inhaled corticosteroid. Patients should be instructed in the proper use of their inhaler and their technique should be checked to ensure that the patient can synchronise aerosol actuation with inspiration of breath to obtain optimum delivery of the inhaled drug to the lungs. Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver


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function due to decreased first pass metabolism. The clinical relevance of this to treatment with Pulmicort CFC-free Inhaler is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected. In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa) causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided (see Section 4.5 Interactions with other medicinal products and other forms of interaction). If this is not possible the time interval between administration of the interacting drugs should be as long as possible. A reduction in the dose of budesonide should also be considered.

4.5 Interaction with other medicinal products and other forms of interaction The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide, (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties). Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide.

4.6 Pregnancy and lactation There is no experience with or evidence of safety of propellant HFA 134a in human pregnancy or lactation. However studies of the effect of HFA 134a on reproductive function and embryofetal development in animals have revealed no clinically relevant adverse effects. Pregnancy Results from a large prospective epidemiological study and from worldwide post marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus / newborn child. Animal studies have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk for humans is unknown. There are no relevant clinical data on the use of Pulmicort CFC-free Inhaler in human pregnancy. Administration of Pulmicort CFC-free Inhaler during pregnancy requires that the benefits for the mother be weighed against the risks for the fetus. Pulmicort CFC-free Inhaler should only be used during pregnancy if the expected benefits outweigh the potential risks. Lactation There is no information regarding the passage of budesonide into breast milk. There are no relevant clinical data on the use of Pulmicort CFC-free Inhaler during lactation in humans. Administration of Pulmicort CFC-free Inhaler to women who are breast-feeding requires careful consideration. As it is not known whether budesonide has any harmful effects on the neonate the use of budesonide formulated with propellant HFA 134a (as Pulmicort CFC-free Inhaler) should only be considered in situations where it is felt that the expected benefits to the mother will outweigh any potential risks to the neonate.


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4.7 Effects on ability to drive and use machines Pulmicort CFC-free Inhaler has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects Clinical trials, literature reports and post-marketing experience of orally inhaled budesonide suggest that the following adverse drug reactions may occur:

Common (>1/100, <1/10)

• Mild irritation in the throat • Candida infection in the oropharynx • Hoarseness • Coughing

Rare (>1/10 000, <1/1 000)

• Nervousness, restlessness, depression, behavioural disturbances

• Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and bronchospasm

• Skin bruising

Candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. The incidence should be less with the use of the NebuChamberTM spacer device since this reduces oral deposition. 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 straightaway. Pulmicort CFC-free Inhaler should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infections and impairment of the ability to adapt to stress may also occur. Effects are probably dependent on dose, exposure time, concomitant and previous steroid exposure and individual sensitivity. Prolonged treatment with high doses of inhaled cortiocosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress, such as severe infections or elective surgery. Such patients should be instructed to carry a steroid warning card


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indicating their needs. (See also Section 4.4 Special warnings and precautions for use)

4.9 Overdose The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of HPA axis function. No special emergency action needs to be taken. Treatment with Pulmicort CFC-free Inhaler should be continued at the recommended dose to control the asthma.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Budesonide is a glucocorticosteroid that possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids. Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02. Topical anti-inflammatory effect The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important. A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide, compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract. In a provocation study, pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions. Onset of effect After a single dose of orally inhaled budesonide delivered via dry powder inhaler, improvement of lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment although maximum benefit may not be achieved for up to 4 weeks. Airway reactivity Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients. Exercise-induced asthma Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma. Growth


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Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment (see Section 4.4 Special warnings and precautions for use). HPA axis function Studies in healthy volunteers with inhaled budesonide (administered as a dry powder via Turbohaler) have shown dose-related effects on plasma and urinary cortisol. At recommended doses Pulmicort Turbohaler causes less effect on adrenal function than prednisolone 10 mg, as shown by ACTH tests.

5.2 Pharmacokinetic properties After inhalation of budesonide via pressurised metered dose inhaler, approximately 10% to 15% of the metered dose is deposited in the lungs. The maximal plasma concentration after oral inhalation of a single dose of 800 or 1600 micrograms budesonide was 1.32 and 2.41 nmol/L respectively, and was reached after about 40 minutes. Budesonide undergoes an extensive degree (approximately 90%) of biotransformation in the liver, to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. In a study, 100 mg ketoconazole taken twice daily increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

5.3 Preclinical safety data The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclometasone dipropionate, fluocinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect. Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.


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In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses. Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range. The safe use of norflurane has been fully evaluated in preclinical studies. It is well accepted and used in several pressurised metered dose inhalers, and is essentially non-toxic. Magnesium stearate has a history of safe use in man for many years, which supports the view that magnesium stearate is essentially biologically inert. The safe use of magnesium stearate for inhalation has been fully evaluated in preclinical studies. Inhalation toxicity studies conducted with magnesium stearate in rats (26 weeks) and dogs (4 weeks) did not show signs of toxicity up to doses about 490 and 11000 times higher, respectively, than the maximum exposure achievable during the daily treatment with the new formulation. Furthermore, toxicity studies carried out using Pulmicort pressurised metered dose inhaler have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Norflurane (HFA 134a) - a CFC-free propellant Magnesium stearate.

6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years.

6.4 Special precautions for storage Do not store above 30°C. Always store Pulmicort CFC-free Inhaler so that it stands upright on its brown plastic base (with the valve downwards). The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.

6.5 Nature and contents of container


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The immediate container is an aluminium can which is sealed with a metering valve. The container is assembled with an actuator containing a mouthpiece. The actuator and the mouthpiece are made of polypropylene. Each inhaler delivers 120 metered doses/actuations after initial priming.

6.6 Special precautions for disposal The canister should not be broken, punctured or burnt, even when apparently empty.

7 MARKETING AUTHORISATION HOLDER AstraZeneca UK Ltd., 600 Capability Green Luton LU1 3LU, UK.

8 MARKETING AUTHORISATION NUMBER(S) PL 17901/0246

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 24/09/2008 10 DATE OF REVISION OF THE TEXT

24/09/2008


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Pulmicort CFC-free Inhaler 100 micrograms. ▼

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each metered dose (ex-valve)/actuation contains budesonide 100 micrograms. For full list of excipients, see Section 6.1.

3 PHARMACEUTICAL FORM Pressurised inhalation, suspension. The NebuChamberTM spacer device is the only spacer device to be used with Pulmicort CFC-free Inhaler.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Asthma.

4.2 Posology and method of administration For inhalation use. Adults, including the elderly: 200 micrograms twice daily, in the morning and in the evening. During periods of severe asthma the daily dosage can be increased up to 1600 micrograms. In patients whose asthma is well controlled, the daily dose may be reduced below 400 micrograms but should not go below 200 micrograms. The dose should be reduced to the minimum needed to maintain good asthma control. Children 2-12 years: 200 to 800 micrograms daily in divided doses. A higher strength inhaler (200 microgram) is available for use in children with moderately severe/severe asthma and requiring a dose regimen of Pulmicort CFC-free Inhaler of 800 micrograms as a total daily dose. The dose should be reduced to the minimum needed to maintain good asthma control. Pulmicort CFC-free Inhaler is not recommended for use in children less than 2 years of age. Patients maintained on oral glucocorticosteroids Pulmicort CFC-free Inhaler may permit replacement or significant reduction in the dosage of oral glucocorticosteroids while maintaining asthma control.


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For further information on the withdrawal of oral corticosteroids see Section 4.4 (Special warnings and precautions for use). Method of Administration Instructions for the correct use of Pulmicort CFC-free Inhaler Note: It is important to instruct the patient to:

• Carefully read the detailed instructions for use and refer to the accompanying pictograms in the Patient Information Leaflet which is packed with each inhaler.

• Take his/her time when using the inhaler and not to rush through the individual steps.

• To practise using the inhaler in front of the mirror. Advise the patient that if any mist is seen coming from the top of the inhaler or from the mouthpiece it may mean that he/she has not inhaled the medicine properly.

• Shake the inhaler thoroughly for a few seconds to mix the contents of the inhaler properly.

• Prime the inhaler by actuating it twice into the air when the inhaler is new, if it has been dropped, or when it has not been used for more than 7 days.

• Place the mouthpiece in the mouth. While breathing in slowly and deeply, press the canister firmly to release the medication. Advise the patient that he/she may need to use both hands to operate the inhaler. Continue to breathe in and hold the breath for as long as is comfortable.

• Remove the inhaler from the mouth before breathing out; the patient must be advised that he/she must not breathe out through the inhaler.

• If a second or subsequent actuation is required the patient should be advised to wait for about half a minute and then replace the mouthpiece in the mouth and repeat the instructions at the preceding two bullet points, the sixth and seventh bullet points as listed.

• Rinse the mouth out with water after inhaling the prescribed dose to minimise the risk of oropharygeal thrush.

• Clean the mouthpiece of the inhaler regularly, at least once a week. Remove the dust cap and the aerosol canister. Clean the plastic actuator and dust cap with a dry cloth or tissue. Refer to the detailed instructions for cleaning in the Patient Information Leaflet, which is packed with each inhaler. Advise the patient that the metal aerosol canister should not be put into water or be cleaned with water.

• Always store Pulmicort CFC-free Inhaler so that it stands upright on its brown plastic base (with the valve downwards).

The use of Pulmicort CFC-free Inhaler with the NebuChamberTM spacer device is recommended to enable patients with difficulty in co-ordinating


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inhalation with actuation, such as infants, young children, the poorly co-operative or the elderly, to derive greater therapeutic benefit. The mouthpiece of Pulmicort CFC-free Inhaler fits directly into the NebuChamber spacer device. Pulmicort CFC-free Inhaler should only be used with the NebuChamber spacer device, it should NOT be used with any other spacer device as an alternative device may alter the pulmonary deposition of budesonide. A spacer device should always be available together with a pressurised metered dose inhaler when a pressurised metered dose inhaler is prescribed for use by a child. Instructions for the correct use of Pulmicort CFC-free Inhaler with the NebuChamberTM spacer device. Note: It is important to instruct the patient to:

• Carefully read the instructions for use in the Patient Information Leaflet, which is packed with each inhaler.

• Carefully read the instructions for use in the instruction leaflet, which is packed with each spacer device.

On actuation of the aerosol the dose is released into the inhalation chamber. The inhalation chamber is then emptied by two slow deep breaths. Young children may need to breathe 5–10 times through the mouthpiece. For further doses the procedure is repeated. It is important to explain that when a small child is using the NebuChamber spacer device a parent or carer should hold and support the spacer device in the child’s mouth to ensure that the child breathes through the spacer device properly. For young children who are unable to breathe through the mouthpiece, a face mask can be used. Compatible face masks are available separately and care should be taken to ensure a good fit is achieved.

4.3 Contraindications History of hypersensitivity to budesonide or any of the excipients. Active pulmonary tuberculosis. Special care is needed in patients with quiescent pulmonary tuberculosis and with fungal and viral infections in the airways.

4.4 Special warnings and precautions for use Patients not dependent on steroids: Treatment with the recommended doses of budesonide usually gives a therapeutic benefit within 7 days. However, certain patients may have an excessive collection of mucus secretion in the bronchi. In these cases, a short course of oral corticosteroids (usually 1 to 2 weeks) should be given in addition to the aerosol. After the course of the oral drug, the inhaler alone should be sufficient therapy. Steroid-dependent patients: Transfer of patients on oral steroids to treatment with Pulmicort CFC-free Inhaler demands special care, mainly due to the slow restitution of the disturbed hypothalamic-pituitary adrenocortical axis function, caused by extended treatment with oral corticosteroids. When the


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Pulmicort CFC-free Inhaler treatment is initiated the patient should be in a relatively stable phase. A high dose of budesonide, in combination with the previously used oral steroid dose, should be given for about 10 days. The down titration dose should be selected at the discretion of the physician, based on the patient’s disease and former steroid intake. For example, a down titration with 5 mg prednisolone per day, on a weekly basis; this reduction will mean that a daily dose of 20 mg per day would be reduced to 15 mg per day in the first week, 10 mg per day in the second week etc. The oral dose is thus reduced to the lowest level that, in combination with budesonide, provides maintained or improved asthma control. In many cases it may be possible to completely substitute the oral steroid with inhaled budesonide; however some patients may have to be maintained on a low dose of oral steroid together with inhaled budesonide. During the withdrawal of oral steroids some patients may experience uneasiness and may feel generally unwell in a non-specific way even though respiratory function is maintained or improved. Patients should be encouraged to continue with inhaled budesonide whilst withdrawing the oral steroid unless there are clinical signs to indicate the contrary. Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy and hence oral steroid-dependent patients transferred to inhaled budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances HPA axis function should be monitored regularly. These patients should be instructed to carry a steroid warning card indicating their needs. Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress such as severe infections or elective surgery. Such patients should be instructed to carry a steroid warning card indicating their needs (See also Section 4.8.Undesirable effects). Rapid reduction in the dose of steroids can induce acute adrenal crisis. Symptoms and signs which might be seen in acute adrenal crisis may be somewhat vague but may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension and hypoglycaemia. Treatment with supplementary systemic steroids or inhaled budesonide should not be stopped abruptly. During transfer from oral therapy to Pulmicort CFC-free Inhaler, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary. Exacerbations of asthma caused by bacterial infections are usually controlled by appropriate antibiotic treatment and possibly increasing the budesonide dosage or, if necessary, by giving systemic steroids.


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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 straightaway. Pulmicort CFC-free Inhaler should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained. It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids be regularly monitored. If growth is slowed therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist. Pulmicort CFC-free Inhaler is not intended for rapid relief of acute episodes of asthma or symptoms of asthma. In these situations an inhaled short-acting bronchodilator is required. Patients should be advised to have such ‘rescue’ medication with them at all times. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual and respiratory symptoms persist, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy e.g. higher doses of inhaled budesonide, the addition of a long-acting beta agonist or a course of oral glucocorticosteroids. Patients should be reminded of the importance of taking prophylactic therapy regularly, even when they are asymptomatic. Patients should also be reminded of the risk of oropharyngeal Candida infection, due to drug deposition in the oropharynx. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. Oropharyngeal Candida infection usually responds to topical anti-fungal treatment without the need to discontinue the inhaled corticosteroid. Patients should be instructed in the proper use of their inhaler and their technique should be checked to ensure that the patient can synchronise aerosol actuation with inspiration of breath to obtain optimum delivery of the inhaled drug to the lungs. Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Pulmicort CFC-free Inhaler is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected. In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the


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intestinal mucosa) causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided (see Section 4.5 Interactions with other medicinal products and other forms of interaction). If this is not possible the time interval between administration of the interacting drugs should be as long as possible. A reduction in the dose of budesonide should also be considered.

4.5 Interaction with other medicinal products and other forms of interaction The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide, (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties). Other potent inhibitors of CYP3A4 are also likely to markedly increase plasma levels of budesonide.

4.6 Pregnancy and lactation There is no experience with or evidence of safety of propellant HFA 134a in human pregnancy or lactation. However studies of the effect of HFA 134a on reproductive function and embryofetal development in animals have revealed no clinically relevant adverse effects. Pregnancy Results from a large prospective epidemiological study and from worldwide post marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus / newborn child. Animal studies have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk for humans is unknown. There are no relevant clinical data on the use of Pulmicort CFC-free Inhaler in human pregnancy. Administration of Pulmicort CFC-free Inhaler during pregnancy requires that the benefits for the mother be weighed against the risks for the fetus. Pulmicort CFC-free Inhaler should only be used during pregnancy if the expected benefits outweigh the potential risks. Lactation There is no information regarding the passage of budesonide into breast milk. There are no relevant clinical data on the use of Pulmicort CFC-free Inhaler during lactation in humans. Administration of Pulmicort CFC-free Inhaler to women who are breast-feeding requires careful consideration. As it is not known whether budesonide has any harmful effects on the neonate the use of budesonide formulated with propellant HFA 134a (as Pulmicort CFC-free Inhaler) should only be considered in situations where it is felt that the expected benefits to the mother will outweigh any potential risks to the neonate.

4.7 Effects on ability to drive and use machines Pulmicort CFC-free Inhaler has no or negligible influence on the ability to drive and use machines.


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4.8 Undesirable effects Clinical trials, literature reports and post-marketing experience of orally inhaled budesonide suggest that the following adverse drug reactions may occur:

Common (>1/100, <1/10)

• Mild irritation in the throat • Candida infection in the oropharynx • Hoarseness • Coughing

Rare (>1/10 000, <1/1 000)

• Nervousness, restlessness, depression, behavioural disturbances

• Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and bronchospasm

• Skin bruising

Candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dose will minimise the risk. The incidence should be less with the use of the NebuChamberTM spacer device since this reduces oral deposition. 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 straightaway. Pulmicort CFC-free Inhaler should be discontinued immediately, the patient should be assessed and an alternative therapy instituted if necessary. Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing’s Syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Increased susceptibility to infections and impairment of the ability to adapt to stress may also occur. Effects are probably dependent on dose, exposure time, concomitant and previous steroid exposure and individual sensitivity. Prolonged treatment with high doses of inhaled cortiocosteroids, particularly higher than recommended doses, may also result in clinically significant adrenal suppression. Therefore additional systemic corticosteroid cover should be considered during periods of stress, such as severe infections or elective surgery. Such patients should be instructed to carry a steroid warning card indicating their needs. (See also Section 4.4 Special warnings and precautions for use)

4.9 Overdose The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of HPA axis function. No special emergency


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action needs to be taken. Treatment with Pulmicort CFC-free Inhaler should be continued at the recommended dose to control the asthma.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Budesonide is a glucocorticosteroid that possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids. Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02. Topical anti-inflammatory effect The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important. A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide, compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract. In a provocation study, pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions. Onset of effect After a single dose of orally inhaled budesonide delivered via dry powder inhaler, improvement of lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment although maximum benefit may not be achieved for up to 4 weeks. Airway reactivity Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients. Exercise-induced asthma Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma. Growth Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment (see Section 4.4 Special warnings and precautions for use). HPA axis function Studies in healthy volunteers with inhaled budesonide (administered as a dry powder via Turbohaler) have shown dose-related effects on plasma and


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urinary cortisol. At recommended doses Pulmicort Turbohaler causes less effect on adrenal function than prednisolone 10 mg, as shown by ACTH tests.

5.2 Pharmacokinetic properties After inhalation of budesonide via pressurised metered dose inhaler, approximately 10% to 15% of the metered dose is deposited in the lungs. The maximal plasma concentration after oral inhalation of a single dose of 400 or 800 micrograms budesonide was 0.84 and 1.53 nmol/L respectively, and was reached after about 35 minutes. Budesonide undergoes an extensive degree (approximately 90%) of biotransformation in the liver, to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. In a study, 100 mg ketoconazole taken twice daily increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

5.3 Preclinical safety data The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclometasone dipropionate, fluocinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect. Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man. In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses. Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor


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density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range. The safe use of norflurane has been fully evaluated in preclinical studies. It is well accepted and used in several pressurised metered dose inhalers, and is essentially non-toxic. Magnesium stearate has a history of safe use in man for many years, which supports the view that magnesium stearate is essentially biologically inert. The safe use of magnesium stearate for inhalation has been fully evaluated in preclinical studies. Inhalation toxicity studies conducted with magnesium stearate in rats (26 weeks) and dogs (4 weeks) did not show signs of toxicity up to doses about 490 and 11000 times higher, respectively, than the maximum exposure achievable during the daily treatment with the new formulation. Furthermore, toxicity studies carried out using Pulmicort pressurised metered dose inhaler have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Norflurane (HFA 134a) - a CFC-free propellant Magnesium stearate.

6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years.

6.4 Special precautions for storage Do not store above 30°C. Always store Pulmicort CFC-free Inhaler so that it stands upright on its brown plastic base (with the valve downwards). The canister contains a pressurised liquid. Do not expose to temperatures higher than 50°C. Do not pierce the canister.

6.5 Nature and contents of container The immediate container is an aluminium can which is sealed with a metering valve. The container is assembled with an actuator containing a mouthpiece. The actuator and the mouthpiece are made of polypropylene. Each inhaler delivers 120 metered doses/actuations after initial priming.

6.6 Special precautions for disposal UKPAR AstraZeneca UK Ltd, Pulmicort CFC-free Inhalers 100 and 200 micrograms

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The canister should not be broken, punctured or burnt, even when apparently empty.

7 MARKETING AUTHORISATION HOLDER AstraZeneca UK Ltd., 600 Capability Green Luton LU1 3LU, UK.

8 MARKETING AUTHORISATION NUMBER(S) PL 17901/0247

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 24/09/2008 10 DATE OF REVISION OF THE TEXT

24/09/2008


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PATIENT INFORMATION LEAFLET


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LABELLING


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