Public Assessment Report Scientific discussion SE/H/1689/01/DC

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1 Public Assessment Report Scientific discussion Budesonide/Formoterol Sandoz (budesonide, formoterol fumarate dehydrate) SE/H/1689/01/DC This module reflects the scientific discussion for the approval of Budesonide/Formoterol Sandoz. The procedure was finalised on For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION Sandoz A/S has applied for a marketing authorisation for Budesonide/Formoterol Sandoz Inhalation powder, 160 µg/dose (budesonide), 4,5 µg/dose (formoterol fumarate dehydrate). The active substances are budesonide and formoterol fumarate dehydrate. The specific properties of budesonide and formoterol allow the combination to be used either as maintenance and reliever therapy or as maintenance treatment of asthma. Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Formoterol is a selective β2 adrenoceptor agonist that, when inhaled, results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. For approved indications, see the Summary of Product Characteristics. The marketing authorisation has been granted pursuant to Article 10(3) of Directive 2001/83/EC. For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to the marketing authorisation, please see section VI. II. QUALITY ASPECTS II.1 Drug Substance The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described. The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies confirm the retest period. II.2 Medicinal Product The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics. The manufacturing process has been sufficiently described and critical steps identified. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. 2/8

3 Stability studies have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4. III. NON-CLINICAL ASPECTS Pharmacodynamic, pharmacokinetic and toxicological properties of budesonide and formoterol fumarate are well known. As budesonide and formoterol fumarate are widely used, wellknown active substances, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. Environmental Risk Assessment (ERA) Since Budesonide/Formoterol Sandoz is intended for generic substitution, this is not likely to lead to an increased exposure to the environment. The Applicant submitted sales data from the concerned member states, showing that there was no significant increase in sales, and accordingly no increased exposure to the environment. There are no objections to an approval of Budesonide/Formoterol Sandoz from a non-clinical point of view. IV. CLINICAL ASPECTS Therapeutic equivalence of the developed medicinal product with the reference medicinal product Symbicort Turbuhaler was evaluated in accordance with European guidance, especially the Guideline for Orally Inhaled Products (OIPs) CPMP/EWP/4151/00 Rev. 1 of 22 January 2009 based on the comparative evaluation of in vitro data and a pivotal pharmacokinetic (PK) safety plus pulmonary deposition study (Study PWDI-10). Equivalent device characteristics of the test and reference DPI were shown in a flow rate study in the intended patient population (Study PWDI-3). IV.1 Pharmacokinetics The applicant has performed one pivotal pharmacokinetic study with the final formulation. Study PWDI-10 is a pivotal PK study, which was performed to assess the lung deposition and systemic safety of the concerned product Budesonide/Formoterol 160 μg/4.5 μg DPI HEXAL in comparison with the reference product Symbicort Turbuhaler. Study PWDI-10 was a randomised, four-way single-dose crossover study conducted in 68 healthy volunteers under fasting conditions. In each study period a single dose of 640 μg/18 μg budesonide/formoterol (4 inhalations of 160 μg/4.5 μg budesonide/formoterol fumarate dehydrate) of each product was administered via oral inhalation under fasting conditions, excluding the gastrointestinal absorption by charcoal blockade in two study periods. Blood-samples were collected pre-dose and up to 12 h (budesonide) and 24 h (formoterol). Plasma concentrations of budesonide and formoterol were determined with validated LC/MS/MS methods. The results are presented below. 3/8

4 Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, median, range) for budesonide with charcoal, n=65. Treatment AUC 0-t C max pg*h/ml pg/ml Test 4682± ± Reference 4784± ± *Ratio (90% CI) ( ) ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration time for maximum plasma concentration *calculated based on ln-transformed data h - Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) for budesonide without charcoal, n=66. Treatment AUC 0-t C max pg*h/ml pg/ml Test 5403± ± Reference 5284± ± *Ratio (90% CI) ( ) ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration time for maximum plasma concentration *calculated based on ln-transformed data h - Table 3. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, median, range) for formoterol with charcoal, n=65. Treatment AUC 0-t C max pg*h/ml pg/ml Test 99.26± ± Reference ± ± *Ratio (90% CI) ( ) ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration time for maximum plasma concentration h - 4/8

5 *calculated based on ln-transformed data Table 4. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range) for formoterol without charcoal, n=66. Treatment AUC 0-t C max pg*h/ml pg/ml Test ± ± Reference ± ± *Ratio (90% CI) ( ) ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration time for maximum plasma concentration *calculated based on ln-transformed data Bioequivalence was demonstrated since the 90% confidence interval for the AUC0-t and Cmax ratio of the test and reference products, for both budesonide and formoterol, with and without charcoal blockade, fell within the conventional acceptance range of %. h - IV.2 Pharmacodynamics There are no new data. IV.3 Clinical efficacy One clinical study has been conducted with the aim to evaluate flow-rate dependency of the inhalation device of the test product in comparison to the reference product in the intended patient population. Study PWDI-3 was an open-label, randomized, two-way crossover clinical study with empty GyroHaler Plus and Symbicort Turbuhaler dry powder inhaler devices (DPIs) to evaluate flow profiles in adult subjects with severe COPD, adult subjects with severe persistent asthma, children with moderate asthma and healthy adult subjects. The primary parameter for evaluation was PIF generated through the respective DPIs. PIF-values (primary endpoint) were comparable between the test and the reference device in all subgroups. Mean PIF were above 75 L/min in each subgroup. Overall there were no marked differences in PIF between the different populations. It can be concluded that the device can be adequately handled and emptied by a variety of patient categories. IV.4 Risk Management Plans 5/8

6 The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Budesonide/Formoterol Sandoz. Safety specification Summary table of safety concerns as approved in RMP Pharmacovigilance Plan Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed. Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed. Summary of the RMP The RMP is approved. An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures. Periodic Safety Update Report (PSUR) Active substance is currently listed in the published EURD list With regard to PSUR submission, the MAH should take the following into account: PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. 6/8

7 For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification. VI. USER CONSULTATION A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Symbicort Turbuhaler, SE/H/229/01-02/II/35, SE/H/230/01/II/027. The bridging report submitted by the applicant has been found acceptable. VII. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on quality, pharmacokinetic and clinical data presented therapeutic similarity with the reference product Symbicort Turbuhaler was confirmed. The benefit/risk balance is thus deemed positive. List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment N/A List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC N/A VIII. APPROVAL The Decentralised procedure for Budesonide/Formoterol Sandoz Inhalation powder, 160 µg/dose (budesonide), 4,5 µg/dose (formoterol fumarate dehydrate) was positively finalised on /8

8 Public Assessment Report Update Procedure number* Scope Product Information affected Date of end of procedure Approval/ non approval Summary/ Justification for refuse *Only procedure qualifier, chronological number and grouping qualifier (when applicable) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: