Decentralised Procedure. Public Assessment Report. Nurofen Immedia 200mg Weichkapseln Ibuprofen DE/H/1482/001/DC

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Nurofen Immedia 200mg Weichkapseln Ibuprofen DE/H/1482/001/DC Applicant: Reckitt Benckiser Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

2 TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 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... 5 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT /7 Public AR

3 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 Number for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA Nurofen Immedia 200mg Weichkapseln Ibuprofen M01AE mg Soft Capsules DE/H/1482/001/DC Germany AT, BG,CY,CZ,EE,EL,FI,FR,HU,IS,LT,LU,LV, MT,NL,PL,RO,,SK Reckitt Benckiser Deutschland GmbH, Theodor-Heuss- Anlage 12, Mannheim, Germany Reckitt Benckiser Healthcare International Ltd. Thane Road, Nottingham, NG90 2 DB, UK 3/7 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Nurofen Express 200 mg Soft Capsules in the indication For the symptomatic relief of mild to moderate pain, such as headache, period pain, dental pain, and fever and pain in the common cold. is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of ibuprofen, under 4 different trade names. In this overview, for consistency the name Nurofen Express 200 mg Soft Capsules is used. However, the applicant agreed to change the name to Nurofen Immedia. The originator product is Nurofen 200 mg tablets by Reckitt Benckiser Healthcare International Ltd., registered since May II.2 About the product Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) which was first licensed in 1983 for OTC use for acute pain. This marketing application is for a new presentation of ibuprofen, Nurofen Express 200 mg Soft Capsules (also called ibuprofen liquigel) which contains 200 mg ibuprofen in a liquid form. Ibuprofen, at a daily dose of 1200 mg or below, acts predominantly as an analgesic and antipyretic, although it exhibits anti-inflammatory properties at higher doses cumulatively. The recommended oral dose of Nurofen Express 200 mg Soft Capsules is the same as that for Nurofen 200 mg Tablets. This also varies from country to country but is generally an initial dose of two capsules. This should be followed, if necessary, additional doses of one or two capsules, up to a maximum of six capsules (equivalent to 1200 mg ibuprofen acid) in any 24-hour period. Nurofen Express 200 mg Soft Capsules are contraindicated for children under 6 years of age. The indication for Nurofen Express 200 mg Soft Capsules for the symptomatic relief of mild to moderate pain such as headache, period pain, dental pain, and fever and pain in the common cold is accepted. II.3 General comments on the submitted dossier This is a hybrid application, according to article 10.3 of Directive 2001/83/EC for a medicinal product referring to a so-called reference medicinal product with a Marketing Authorisation in a Member State or in the Community (new pharmaceutical form). Two bioavailability studies, reference numbers NL0601 and NL0703 have been performed with the new soft capsules. Both compared the rate and extent of absorption of Nurofen Express Soft Capsules against Nurofen Tablets and were performed in accordance with the CHMP Note for Guidance on Bioavailability and Bioequivalence`. Neither study was expected to demonstrate true bioequivalence as it was anticipated in view of the design characteristics of the new product that the values for t max and C max would be significantly different. The submitted documentation in relation to the proposed product is of sufficient high quality in view of the current European regulatory requirements. 4/7 Public AR

5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. For the manufacturer A the RMS is assured that acceptable standards of GMP are in place for the production of this medicinal product. The RMS has accepted copies of current manufacturer authorisations issued by the Dutch inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For the manufacturer B the RMS is assured that acceptable standards of GMP are in place for the packaging and batch release of this medicinal product. A manufacturer s / importer s licence issued by the British MHRA, dated 4 th June 2007, showing the permission to act for batch release and packaging of soft capsules is presented. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The active substance ibuprofen can be obtained from two manufacturers, both holding certificates of suitability issued by the EDQM. Therefore no real difficulties in the quality of the active substance are presumed and no intense look on the quality of the active substance was done during this procedure because this was still done by the EDQM. Drug Product Nurofen Immedia 200 mg is a typical medicinal product based on soft gelatine capsules. The soft capsule shell itself is made as usual from gelatine according the well known Deby Scherrer (rotary dye) method. Therefore with view to the production method of the soft capsules no serious difficulties in the quality are expected. Ibuprofen is solved in macrogol using potassium hyroxide to neutralise the propionic acid moiety of the active substance. The generation of macrogol esters with ibuprofen is minimised because only around half the amount of potassium hydroxide necessary to neutralise ibuprofen completely is added. Moreover, the generation of the esters is controlled by the release and stability specification. A marketing authorisation is granted. III.2 Nonclinical aspects Pharmacology, Pharmacokinetics, Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well known. As ibuprofen is a widely used, well-known active substance, no further non-clinical studies are required and the applicant provides none. An adequate non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology of ibuprofen is included in the application. Environmental Risk Assessment The applicant commits to conduct data concerning the environment risk by ibuprofen to sediment dwelling organisms, before the first commercial batch of product is launched to markets (see section VI.1). 5/7 Public AR

6 III.3 Clinical aspects As ibuprofen is a widely used, well-known active substance, no further clinical studies are required for this application and the applicant provides none. Overview based on literature review is, thus, appropriate. Pharmacokinetics To support the application, the applicant has submitted as report 2 bioequivalence studies. Both studies were randomised, single-dose, 2- or 3-way crossover, open label pharmacokinetic studies in normal healthy volunteers. Study NL0601 compared two ibuprofen formulations: Nurofen 200 mg Tablets (the Reference product) and Nurofen 200 mg Soft Capsules (the Test product). In study NL0703, a third study arm consisting of ibuprofen lysine 342 mg tablets, equivalent to 200 mg ibuprofen, was incorporated as the comparator product. Based on the submitted bioequivalence studies Nurofen Express 200 mg Soft Capsules is considered bioequivalent with Nurofen tablets as far as the extent of absorption as indicated by AUC0-t and AUC0-inf is concerned. Neither study was expected to demonstrate true bioequivalence as it was anticipated in view of the design characteristics of the new product that the values for tmax and Cmax would be significantly different. Although study NL0601 confirmed faster absorption from the soft capsules, the difference in tmax values was only 25 minutes, which was less than expected. Comparison of the median tmax value indicated that the value of 60 minutes for the tablets was at the bottom end of the normal range for ibuprofen and lower than in other Reckitt Benckiser studies with this formulation. This might be due to the mode of tablet intake which was two tablets at once with 200 ml of water. As well as repeating the original study, study NL0703, was designed to provide further supporting evidence of faster absorption. This was done by modifying the pharmacokinetic sampling schedule to better define tmax for standard ibuprofen and by including additional secondary end-points such as lag time and plasma concentrations at 5 and 10 minutes post-dose as well as absorption (AUC) at times up to 30 minutes post-dose. In addition this study investigated whether the soft capsules were bioequivalent to a currently licensed formulation of the rapidly absorbed lysine salt of ibuprofen (Nurofen Express) containing 324 mg ibuprofen lysine, equivalent to 200 mg ibuprofen acid. The difference in tmax values in comparison to Nurofen tablets was 50 minutes. As further support for speed of absorption, Cmax and tmax values for Nurofen Express Soft Capsules were similar to the fast-absorbed ibuprofen lysine tablets. It is clear from combining the results of both studies that the soft capsules are absorbed faster than the tablets and in both studies the differences in tmax were statistically significant. Clinical safety With regard to the safety analysis, there was no significant difference between the test and reference preparation. The higher Cmax is not supposed to be associated with increased adverse events since ibuprofen has a wide therapeutic window. Both Nurofen Express 200 mg Soft Capsules and Nurofen 200 mg Tablets have a recommended initial posology of 400 mg of ibuprofen. In clinical practice, higher doses of ibuprofen ranging from mg are often given resulting in much higher Cmax values than observed in this study. Furthermore, other ibuprofen products, which achieved Cmax similar to that of ibuprofen soft capsules are currently licensed by Reckitt Benckiser Healthcare International and other companies in the EU (see also tables and of Clinical Overview). The applicant makes reference to Nurofen Liquid Capsules (200 mg ibuprofen) marketed in the UK since Nurofen Express is quasi identical to the UK Nurofen Express Liquid Capsules, the main difference being a slight difference in the quantity of the excipoients Macrogol and potassium hydroxide. 6/7 Public AR

7 During the period October 2006 to September 2007, 21 million packs of Nurofen suspension and 97 million packs of Nurofen tablets/caplets/capsules were manufactured, out of which 18.8 million packs of Nurofen Liquid Capsules. No special risk of adverse events was identified in post-marketing data Pharmacovigilance system The Applicant has provided documents that set out a detailed description of the system of pharmacovigilance (Version dated 17 November 2008). A statement signed by the Applicant and the qualified person for pharmacovigilance, indicating that the Applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the Applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union 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. IV. BENEFIT RISK ASSESSMENT From the clinical point of view the application contains an adequate review of published clinical data. Based on the submitted bioequivalence studies Nurofen Express 200 mg Soft Capsules is considered bioequivalent with Nurofen tablets as far as the extent of absorption as indicated by AUC0-t and AUC0-inf is concerned. Neither study was expected to demonstrate true bioequivalence as it was anticipated in view of the design characteristics of the new product that the values for tmax and Cmax would be significantly different. It is clear from combining the results of both studies that ibuprofen delivered by the soft capsules is absorbed faster than ibuprofen delivered by the tablets and in both studies the differences in tmax were statistically significant. The benefit/risk profile is considered positive and the following indication is accepted: For the symptomatic relief of mild to moderate pain, such as headache, period pain, dental pain and fever and pain in the common cold. The application is approved. 7/7 Public AR