Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended.

Transcription

1 Public Assessment Report for paediatric studies submitted in accordance with Article 45 of Regulation (EC) No1901/2006, as amended Bricanyl () DK/W/0017/pdWS/001 Rapporteur: Denmark Finalisation procedure (day 120): September 5 th, 2013 Date of finalisation of PAR November 1 st, 2013 DK/W/0017/pdWS/001 Page 1/15

2 TABLE OF CONTENTS I. Executive Summary... 4 II. RecommendatioN... 4 III. INTRODUCTION... 4 IV. SCIENTIFIC DISCUSSION... 5 IV.1 Information on the pharmaceutical formulation used in the clinical study(ies)... 5 IV.2 Non-clinical aspects... 5 IV.3 Clinical aspects... 5 V. MEMBER STATES Overall Conclusion AND RECOMMENDATION VI. List of Medicinal products and marketing authorisation holders involved DK/W/0017/pdWS/001 Page 2/15

3 ADMINISTRATIVE INFORMATION Invented name of the medicinal product(s): INN (or common name) of the active substance(s): MAH (s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): See section VI See section VI R 03 CC 03 (systemic use), R 03 AC 03 (inhalation) Tablets 5 mg Prolonged release tablets 5 and 7.5 mg Oral solution 0.3 mg/ml Solution for injection 0.5 mg/ml Turbuhaler 0.25 and 0.5 mg/dose Nebuliser solution 2.5 mg/ml DK/W/0017/pdWS/001 Page 3/15

4 I. EXECUTIVE SUMMARY Only one MAH (AstraZenaca) has presented completed paediatric studies for terbutaline sulfate, where two additional studies, not previously submitted to any regulatory agency, were submitted. These two new studies did not change the overall benefit-risk profile of terbutaline sulfate, nor did they give rise to new indications. No SmPC and PL changes are proposed. Summary of outcome No change Change New study data: <section(s) xxxx, xxxx> New safety information: <section(s) xxxx, xxxx> Paediatric information clarified: <section(s) xxxx, xxxx> New indication: <section(s) xxxx, xxxx> II. RECOMMENDATION 1 No further action is required. III. INTRODUCTION One single MAH has submitted 79 completed paediatric studies for terbutaline sulfate, hereafter terbutaline, in accordance with Article 45 of the Regulation (EC)No 1901/2006, as amended on medicinal products for paediatric use. A short critical expert overview has also been provided. The MAH states that the submitted paediatric studies do not influence the benefit risk for Bricanyl and that there is no consequential regulatory action. In addition, the following documentation has been included as per the procedural guidance: 1 The recommendation from section V can be copied in this section. DK/W/0017/pdWS/001 Page 4/15

5 - A line listing - An annex including SPC wording of sections 4.1 and 4.2 related to the paediatric use of the medicinal product in different European countries. The Applicant has provided a literature study including search criteria, which is acknowledged. The search criteria are comprehensive and acceptable. The results do not indicate a change in the approved indications. IV. IV.1 SCIENTIFIC DISCUSSION Information on the pharmaceutical formulation used in the clinical study(ies) Bricanyl is indicated for the treatment of bronchial asthma, chronic bronchitis, emphysema and other lung diseases where bronchospasm is a complicating factor. In some countries Bricanyl is approved for the inhibition of preterm labour. Bricanyl is available for systemic or inhaled use in the following pharmaceutical forms and strengths in European Economic Area (EEA) states. For systemic use: tablets 5 mg, prolonged release tablets 5 and 7.5 mg, oral solution 0.3 mg/ml, and solution for injection 0.5 mg/ml. For inhalation: Turbuhaler (inhalation powder) 0.25 and 0.5 mg/dose and Nebuliser solution 2.5 mg /ml. Bricanyl tablets and solution for injection were the first pharmaceutical forms to be approved. The first approval was in Denmark, on 30 June Bricanyl has been authorised via national procedures and is currently approved for marketing in at least one of the pharmaceutical forms above in 18 EEA states. The approved age limits for the different pharmaceutical forms vary from country to country. IV.2 Non-clinical aspects 1. Introduction No non-clinical studies have been submitted. IV.3 Clinical aspects 1. Introduction The MAH (AstraZeneca) has provided a clinical overview that reviews relevant paediatric information from Bricanyl (terbutaline) clinical studies not yet submitted to all EU authorities. AstraZeneca has provided a line listing of all Bricanyl clinical studies performed by AstraZeneca DK/W/0017/pdWS/001 Page 5/15

6 that included paediatric patients, a listing that included 76 studies. Only two of these studies have not previously been submitted to European regulatory authorities. The designs of the 2 relevant studies are summarised below: - Study ; A comparison of terbutaline turbuhaler and salbutamol aerosol inhaler in asthmatic children with reversible airways obstruction. - Study ; Effect of controlled-release terbutaline and budesonide alone and in combination in asthmatics. A multi-centre study. 2. Clinical studies Study ; A comparison of terbutaline turbuhaler and salbutamol aerosol inhaler in asthmatic children with reversible airways obstruction. Description This was a randomised, open, cross-over study comparing terbutaline (Bricanyl Turbuhaler) 500 μg tid and salbutamol 200 μg tid via pressurised metered-dose inhaler (pmdi), each given for 2 weeks to asthma patients aged 5 to 12 years with 10% reversibility and requiring regular inhaled bronchodilator therapy. Methods Objective(s) To compare the effects of terbutaline Turbuhaler and salbutamol pmdi on daily lung function and astma symptoms in patients with reversible airways obstruction not previously exposed on a regular basis to either device. To compare the patient acceptability of the two devices. Study design The trial was multicentre open, randomised crossover carried out at three centres. There were to treatment periods of 2 weeks each, preceded by a one week run-in on existing medication. Study population /Sample size DK/W/0017/pdWS/001 Page 6/15

7 Fifty four patients were randomised to treatment. There were 37 males and 17 females with a mean age of 8.4 years (5-12 years) of whom 85% had extrinsic astma. One patient discontinued after terbutaline treatment. Treatments The investigational drug was terbulatine 500 mcg/inhalation administered as Terbasmin Turbuhaler, in a dose of 1 inhalation morning, noon and night. The reference therapy was salbutamol 100 mcg/puff administered by metered dose inhaler in a dose of 2 puffs morning, noon and night. Outcomes/endpoints Primary: PEF (morning and evening) Secondary: Diurnal variation Number of extra inhalations of study drug (daytime and nighttime) The patient period preference FEV1, FVC, FEF and PEF measured at each clinic visit Statistical Methods A significance level of 0.05 was used in the analysis to test for treatment differences. In the analysis, both All Patients Treated (APT) and the Per Protocol (PP) approaches were used. Patient were excluded from the APT, if they have not taken at least one dose of treatment in each of the treatment periods and had at least one day of diary data in each treatment period available. Analysis of variance was used to compare terbutaline and salbutamol. Patient period preference was analysed using Prescott s test. The investigator s assessment of the patient s use of the inhaler compared the Turbuhaler and pmdi using the Wilcoxon rank sum test. Results Recruitment/ Number analysed Sixty hospital out-patients were intended to complete the study, however only 54 were enrolled in the study. DK/W/0017/pdWS/001 Page 7/15

8 Baseline data Baseline characteristics could not be found in the study report. There were references to Tables 2 and 3 and an Appendix 1, but these were not to be found. Efficacy results All Patients treated DK/W/0017/pdWS/001 Page 8/15

9 Per Protocol DK/W/0017/pdWS/001 Page 9/15

10 DK/W/0017/pdWS/001 Page 10/15

11 DK/W/0017/pdWS/001 Page 11/15

12 In summary There were no differences with regard to extra inhalations of terbutaline and salbutamol. There were no significant differences between the treatments for FEV1, FVC, FEF or PEF at Clinic visit. For effects 25 patients preferred terbutaline, 14 patients preferred salbutamol, and 14 patients were indifferent. For side-effects 11 patients preferred terbutaline, 4 patients preferred salbutamol and 38 patients were indifferent. Safety results No SAE s were reported. Study ; Effect of controlled-release terbutaline and budesonide alone and in combination in asthmatics. A multi-centre study. Description This was a randomised, double-blind, parallel-group, multi-centre study in 181 patients ages 15 to 72 years, 13 of which were ages The efficacy and safety of oral controlled-release terbutaline 5 mg tablet, inhaled budesonide 200 mcg/dose and inhaled budesonide 200 mcg/dose in combination with oral controlled-release terbutaline 5 mg was investigated as maintenance treatment in astma. Methods Objective(s) The aim of the study was to evaluate the efficacy and safety of oral controlled-release terbutaline 5 mg tablet, inhaled budesonide 200 mcg/dose and inhaled budesonide 200 mcg/dose in combination with oral controlled release terbutaline 5 mg, taken twice daily as maintenance treatment in asthma. Study design Multi-centre, randomised, double-blind, parallel group study with double-dummy technique. The study was to be started with a two week run-in period followed by a 12 week study period. During run-in all patients were to receive Theo-Dur twice daily and Terbutaline pmdi as rescue medication to establish baseline values. DK/W/0017/pdWS/001 Page 12/15

13 Study population /Sample size The intention was to include 240 patients. However, only 181 patients ages 15 to 72 years, 13 of which were ages 15-17, were included. Treatments Theo-Dur 200 mg Terbutaline controlled-release 5 mg tablets Budesonide 200 mcg/dose Rescue medication: Bricanyl pmdi 0.25 mg/dose. Outcomes/endpoints PEF, morning and evening (Primary endpoint) Astma symptoms Number of inhalation of rescue medication and adverse experiences FEV1, FVC, MEF25-75%, PEF, and adverse experiences at Clinic visit. Statistical Methods Data was analysed by analysis of variance followed by pair-wise comparisons between treatments and suitable contrasts. Results Recruitment/ Number analysed 181 patients were included in the study. DK/W/0017/pdWS/001 Page 13/15

14 Baseline data The Applicant has provided the rapporteur with Appendix A form Study (Effect of controlled-release terbutaline and budesonide alone and in combination in asthmatics). The Appendix includes information regarding patient demography, baseline values, FEV at clinic visits, etc. As mentioned previously this study has little value for a paediatric population, since very few patients were less than 18 years. Efficacy results The MAH claims that Budesonide alone or in combination with controlled-release terbutaline statistically significantly improved morning and evening PEF compared with terbutaline alone. The mean change from run-in for morning PEF was -1 L/min for the terbutaline group (not statistically significant), compared with 17 L/min (P=0.002) and 24 L/min (P>0.001), respectively, for the budesonide and budesonide + terbutaline groups. There was also a tendency towards an additive effect when using terbutaline and budesonide compared with budesonide alone, but the difference was not statistically significant. Results for symptom scores were generally in accordance with results for the primary variables, with a statistically significantly greater reduction in night-time symptom score and night-time use of rescue medication in the budesonide and the budesonide + terbutaline groups compared with the terbutaline group. However, the lung function test measured at the clinic visits did not give the same clear results as the diary variables did. Often the differences were not statistically significant. Safety results No serious adverse events were reported during the study. The MAH claims that there were no remarkable over representation of adverse events in any treatment group. There references to Appendix 1, tables 16-19, which cannot be found by the assessor. 3. Discussion on clinical aspects and conclusion The MAH claims that the studies summarised in this document relate to treatment with two formulations of Bricanyl, ie, Bricanyl Turbuhaler and Bricanyl prolonged release tablets. Both these formulations are approved for use in children, although the approvals vary across EEA countries. The studies summarised here confirm the efficacy of terbutaline and the value of combining terbutaline with regular inhaled corticosteroid treatment in the paediatric population of asthma patients. However, Study only has limited relevance to the paediatric age group, since only patients from the age of 15 years and upwards were included in the study. V. MEMBER STATES OVERALL CONCLUSION AND RECOMMENDATION Overall conclusion The MAH has submitted two trials that previously have not been submitted to any regulatory agency/authority. The relevance of study is limited, since only patients from age 15 years were included and only 13 patients were aged However, in the view of member states the presented studies gives no rise to a change in the clinical aspects and the benefit-risk balance of Bricanyl in a paediatric patient population. DK/W/0017/pdWS/001 Page 14/15

15 Recommendation No further action required. VI. LIST OF MEDICINAL PRODUCTS AND MARKETING AUTHORISATION HOLDERS INVOLVED Marketing authorization holder: AstraZeneca Name(s) of the product(s): Bricanyl Pharmaceutical forms and strengths: Tablets 5 mg Prolonged release tablets 5 mg and 7.5 mg Oral solution 0.3 mg/ml Solution for injection 0.5 mg/ml Powder for inhalation 0.25 mg/dose and 0.5 mg/dose Nebuliser solution 2.5 mg/ml DK/W/0017/pdWS/001 Page 15/15