Decentralised Procedure Public Assessment Report Budesonid Sandoz 32 / 64 Mikrogramm/Sprühstoß Nasenspray, Suspension Budesonide DE/H/0933/001-002/DC Applicant: Sandoz Pharmaceuticals GmbH Reference Member State DE
TABLE OF CONTENTS I. INTRODUCTION... 5 II. EXECUTIVE SUMMARY... 5 II.1 Problem statement... 5 II.2 About the product... 5 II.3 General comments on the submitted dossier... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Nonclinical aspects... 6 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 7
ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Member State: Concerned Member States: Applicant: Budesonid Sandoz 32 / 64 Mikrogramm/Sprühstoß Nasenspray, Suspension Budesonide R01AD05 Nasal spray, suspension; 32 µg / 64 µg DE CZ, DK, FR, NL, NO, PL, SE, UK Sandoz Pharmaceuticals GmbH Dieselstr. 5 70839 Gerlingen Germany Budesonide, DE/H/0933/001-002/DC Public AR 3/7
LIST OF ABBREVIATIONS AE BANS CI CMS EU GCP GLP GMP LoQ MedDRA NIS PAR PL PP RMS SAE SAR SmPC TEAE Adverse event Budesonide aqueous nasal spray Confidence interval Concerned Member State European Union Good clinical practice Good laboratory practice Good manufacturing practice List of questions Medical dictionary for regulatory activities Nasal index score Perennial allergic rhinitis Package leaflet Per protocol Reference Member State Serious adverse event Seasonal allergic rhinitis Summary of product characteristics Treatment-emergent adverse event Budesonide, DE/H/0933/001-002/DC Public AR 4/7
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Budesonid Sandoz 32 / 64 Mikrogramm/Sprühstoß Nasenspray, Suspension, indicated in the treatment and prevention of signs and symptoms of seasonal and perennial allergic rhinitis and in the treatment of signs and symptoms of nasal polyps, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement Allergic rhinitis is a persistent (PAR) or seasonal (SAR) allergen induced condition affecting up to an estimated 40 % of the general population. Intranasal corticosteroids as well as systemic or topic anthistamines are accepted therapies of these diseases. Nasal corticosteroids are also commonly used to treat the signs and symptoms of nasal polyps. II.2 About the product The applied products (active ingredient: budesonide) are generic versions of Astra Zeneca s budesonide containing nasal spray, licensed in many member states of the EU. The applicant filed an application for two different strengths, 32 µg and 64 µg, respectively. The applicant states that the applied product is almost identical to the reference product, with the addition of ascorbic acid being the only difference. II.3 General comments on the submitted dossier The clinical overview and the clinical summary summarize the well-known properties of budesonide and the clinical program. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. No new preclinical studies have been performed. The applicant states that the clinical equivalence study has been conducted in accordance with GCP. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance Budesonide micronized is a well-known active substance described in the Ph. Eur. Active substance manufacturer A submitted an Active Substance Master File. Two certificates of suitability, due to different drug substance syntheses, are submitted by active substance manufacturer B. Relevant quality characteristics of the drug substance are specified. The batch results show compliance with the specifications. Stability studies have been performed with the drug substance. No significant changes of the parameters were observed. The stability data support retest-periods of 1 and 3 years, respectively, for the drug substance from manufacturer B. Drug Product The drug product is a nasal spray. The development of the product is described in detail and the choice of active substance and excipients is justified. The validation of the manufacturing process has been successfully performed for the manufacturer. The drug product specifications cover appropriate parameters for this dosage form. The analytical methods are validated. The batch analysis shows that the finished products manufactured meet the specifications. The stability data fully support the shelflife of 24 months. The shelf-life after first opening of the container has been confirmed for a period of three months. Budesonide, DE/H/0933/001-002/DC Public AR 5/7
III.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of budesonide are well known. Since budesonide is a widely used, well known active substance, and the applicant is claiming essential similarity to an already approved product, no further non clinical studies have been submitted. Overview based on literature is thus acceptable. Considering that this application concerns a generic and no new indications are added in this application it is expected that the product will substitute parts of prescriptions of currently marketed drugs. Consequently, no changes in the environmental that are not already known for budesonide nasal spray are to be anticipated. III.3 Clinical aspects Pharmacokinetics The applicant conducted a clinical equivalence study instead of a bioequivalence study, because of the topical mode of action of the applied products. Pharmacodynamics N/A Clinical efficacy The applicant conducted a multicentre, randomised, double-blind, placebo- and active-controlled, fixed-dose, parallel group study (Study 1004/2) to compare efficacy and safety of BANS with European reference product Rhinocort Aqua nasal spray by Astra Zeneca from the polish market. Both treatments were administered at 256 µg/day. The study enrolled male and female patients aged 18 to 65 years with at least a 2-year history of seasonal allergic rhinitis and at least 2 out of three of the following symptoms: blocked nose, runny nose, sneezing during 4 out of 7 days during the 7- to 14 day baseline period. At least 1 out of 3 nasal symptoms were to have a score of 2 during 4 days of the run-in phase. Included patients also had to have a positive skin prick test to seasonal allergens present in the environment. 378 patients were randomised and received study medication. The primary efficacy analysis assessed the difference between active treatments in the change from baseline in nasal index score (NIS) which was calculated as the sum of nasal symptoms. The CI (-0.41, 0.27) for the treatment difference for the change from baseline in NIS in the PP population was within the pre-specified equivalence limits. Therefore equivalence was concluded. Most secondary parameters showed significantly improvements with both active treatments. In direct comparison, both active treatments were not significantly different. This study is considered suitable to establish equivalent efficacy. Clinical safety Treatment-emergent AEs (TEAE) were rather evenly distributed among groups with three patients reporting severe AEs (1 patient in the budesonide: severe dysmenorrhoea, 2 patients in the European reference product Rhinocort Aqua nasal spray group: severe somnolence, severe eye allergy). No deaths or SAEs were reported. The vital signs evaluation as well as the laboratory evaluation and the physical examination did not result in any concerns with regard to safety. Pharmacovigilance system The Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. No special risk management plan has been submitted. Due to the well-known properties of budesonide this has been accepted. Budesonide, DE/H/0933/001-002/DC Public AR 6/7
IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data. The therapeutic equivalence study is acceptable. The risk benefit assessment is positive for the adult population. Because of a disagreement between the member states a referral to CMD(h) and an arbitration to CHMP were started on the grounds of potential serious risk to public health. The points to be considered concerned the benefit-risk ratio of Budesonid Sandoz in children. The EC decision was positive and concluded that the benefit-risk ratio is favourable for Budesonid Sandoz in children and that the objection raised by some member states should not prevent the granting of a Marketing Authorisation. The application is approved. For intermediate amendments see current product information. Budesonide, DE/H/0933/001-002/DC Public AR 7/7