Decentralised Procedure

Public Assessment Report

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler

Ipratropium bromide

DE/H/3670/001/DC

(former UK/H/3401/001/DC)

Applicant: Institut Dr. Zoeller

This module reflects the scientific discussion for the approval of IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler. The procedure was finalised at 10.03.2011.

TABLE OF CONTENTS

I. INTRODUCTION ...... 4 II. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 4 II.1 Quality aspects ...... 4 II.2 Non-clinical aspects ...... 5 II.3 Clinical aspects ...... 6 III. OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT ...... 6 ADMINISTRATIVE INFORMATION

Proposed name of the medicinal IPRABRONCH 250 Mikrogramm/ml Lösung für einen product in the RMS Vernebler Name of the drug substance (INN Ipratropium bromide name): Pharmaco-therapeutic group R03BB01 (ATC Code): Pharmaceutical form(s) and Nebuliser Solution; 250 Micrograms per ml strength(s): Reference Number(s) for the DE/H/3670/001/DC (former UK/H/3401/001/DC) Decentralised Procedure Reference Member State: DE (former UK) Concerned Member States: AT

Applicant (name and address) Institut Dr. Zoeller Kriemhildstr. 17 69469 Weinheim Germany

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, DE/H/3670/001/DC Public AR 3/7 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, indicated in  Bronchospasm associated with chronic obstructive pulmonary disease (COPD)  Airways obstruction in patients with acute and chronic asthma, when used concomitantly with inhaled β 2 agonists, is approved.

After changing the RMS, Germany is the new RMS. The former procedure number was UK/H/3401/001/DC.

This application was submitted using Decentralised procedure, with UK as Reference Member State (RMS) and Austria (AT) and Germany (DE) as Concerned Stated (CMS). The application was submitted under Article 10.3 of Directive 2001/83/EC, as amended, as a hybrid application. The reference medicinal product for this application is Atrovent 250 UDVs. 1 ml and Atrovent UDVs, 2 ml (Boehringer Ingelheim Limited, UK) which was first authorised in the UK on 27 August 1986.

Ipratropium bromide is a non-selective antagonist of the muscarine receptors M1, M2, M3, M4 and M5. Although ipratropium bromide blocks all five muscarinic receptor subtypes with similar affinity, it is likely that M3-receptor antagonism alone for the bronchodilating effect. However, the blockade of the M2-receptor subtype allows further release of presynaptic acetylcholine and may antagonise the bronchodilatory effect of blocking the M3-receptor.

No new non-clinical or clinical data have been submitted, which is acceptable given that this is a hybrid application based on an originator product that has been on clinical use for over 10 years.

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacturer, assembly and batch release 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 certificate that acceptable standards of GMP are in place at those sites.

The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 08 March 2011. After a subsequent national phase, a licence was granted in the UK on 26 October 2011.

II. SCIENTIFIC OVERVIEW AND DISCUSSION II.1 Quality aspects Drug substance Ipratropium bromide is the subject of a European Pharmacopoeia monograph. All aspects of the manufacturer and control of the active substance ipratropium bromide monohydrate are covered by a European Directorate for the Quality of Medicine (EDQM) Certificates of Suitability.

Drug product Other ingredients consist of the pharmaceutical excipients sodium chloride, water for injections and concentrated hydrochloric acid (for pH adjustment). Appropriate justification for the inclusion of each excipient has been provided. All excipients comply with their respective European Pharmacopoeia monographs. Suitable batch analysis data have been provided for each excipient, showing compliance with their respective monograph. None of the excipients are sourced from animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients.

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, DE/H/3670/001/DC Public AR 4/7 Pharmaceutical Development The objective of the pharmaceutical development programme was to produce a safe, efficacious, product that was comparable in performance to the originator product, Atrovent 25 UDVs 250 micrograms/ml Nebulizer Solution (Boehringer Ingelheim Limited, UK). The physico-chemical properties of the drug product and the reference product, Atrovent 250 UDVs, 1 ml and Atrovent UDVs, 2 ml (Boehringer Ingelheim Limited, UK) have been found to be comparable. Suitable pharmaceutical development data have been provided for this application. Comparative in-vitro data have been provided for this product and the reference product.

Manufacturing process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated with production-scale batches and has shown satisfactory results.

Control of Finished Product The finished product specification is satisfactory. Test methods have been described and 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 finished product is supplied in sterile unit dose polyethylene ampoules containing either 1 or 2 ml of solution. The product is packaged with the Product Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 10x1 ml, 10x2 ml, 20x1 ml, 20x2 ml, 50x1 ml, 50x2 ml, 60x1 ml and 60x2 ml ampoules. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging. All primary packaging complies with the European pharmacopoeia and relevant regulations regarding use of materials in contact with food.

Stability of the product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. Based on the results, a shelf-life of 3 years has been proposed for the unopened ampoule, with the storage condition “Do not store above 25°C. Store in the original package.”

It has been stipulated that the medicine should be used immediately after opening the ampoule; unused contents should be discarded. The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier.

Bioequivalence As the product provides local therapeutic activity (that is, not systemic), investigation of bioequivalence is not appropriate for this product.

MAA form The MAA form is satisfactory.

Expert report The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier.

II.2 Non-clinical aspects Pharmacology, Pharmacokinetics, Toxicology As the pharmacodynamics, pharmacokinetic and toxicological properties of ipratropium bromide are well-known, no new non-clinical data have been submitted and none are required. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology.

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, DE/H/3670/001/DC Public AR 5/7 Environmental Risk Assessment (ERA) Suitable justification has been provided for non-submission of an Environmental Risk Assessment. As this product is intended for generic substitution with a product that is already marketed, no increase in environmental burden is anticipated- Thus, the justification for non-submission of an Environmental Risk Assessment is accepted.

II.3 Clinical aspects Pharmacokinetics The clinical pharmacology of ipratropium bromide is well known. No clinical studies have been conducted to support the application and none are required for an application of this type. Essential similarity with the originator product is based on the comparative quality attributes of the product. This application is being made under Article 10.3 (hybrid) of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption – in this case – after inhalant administration.

Efficacy The efficacy profile of ipratropium bromide is well-known. The safety profile of ipratropium bromide is reviewed in the clinical overview. No new safety data has been submitted and none are required for this application.

Safety The safety profile of ipratropium bromide is well-known. The safety profile of ipratropium bromide is reviewed in the clinical overview. No new safety data have been submitted with this application and none are required.

Legal Status The medicinal products are intended for prescription only.

User Testing A packages leaflet has been submitted to the MHRA along with results of consultations with target patient groups (“user testing”), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that patients/user are able to act upon the information that it contains.

Summary Pharmacovigilance system and Risk Management Plan The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the service 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. Suitable justification has been provided for not submitting a Risk Management Plan for this product.

Clinical Expert Report The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier.

III. OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of IPRABRONCH are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact in the benefit/risk balance.

NON-CLINICAL No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology of ipratropium bromide are well-known, no additional data were required.

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, DE/H/3670/001/DC Public AR 6/7 EFFICACY No clinical studies have been conducted to support the application and none are required for an application of this type. Essential similarity with the originator product is based in the comparative quality attributes of the product. This application is being made under Article 10.3 (hybrid) of Directive 2001/83/EC, which states that bioequivalence cannot be demonstrated through bioavailability studies for products for local use intended to act without systemic absorption – in this case – after inhalant administration.

SAFETY The safety profile of ipratropium bromide is well-known. No new safety data were submitted and none were required for this application

PRODUCT LITERATURE The SmPC, PILs and labelling are satisfactory and consistent with those for the originator product, where appropriate, and consistent with current guidelines.

BENEFIT/RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with ipratropium bromide is considered to have demonstrated the therapeutic value of the product. The benefit/risk is, therefore, considered to be positive. The application is approved. For intermediate amendments see current product information.

IPRABRONCH 250 Mikrogramm/ml Lösung für einen Vernebler, DE/H/3670/001/DC Public AR 7/7