Decentralised Procedure. Public Assessment Report. Paracetamol-ratiopharm 75 mg Zäpfchen. Paracetamol DE/H/2948/001/DC. Applicant: ratiopharm GmbH

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1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Paracetamol-ratiopharm 75 mg Zäpfchen Paracetamol DE/H/2948/001/DC Applicant: ratiopharm GmbH Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/6 draft Public AR

2 TABLE OF CONTENTS I. INTRODUCTION... 4 I.1 Problem statement... 4 I.2 About the product... 4 I.3 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 4 II. SCIENTIFIC OVERVIEW AND DISCUSSION... 4 II.1 Quality aspects... 4 II.2 Nonclinical aspects... 5 II.3 Clinical aspects... 5 III. BENEFIT RISK ASSESSMENT /6 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) Paracetamol-ratiopharm 75 mg Zäpfchen Paracetamol N02BE01 Suppository DE/H/2948/001/DC DE LU Ratiopharm GmbH Graf-Arco-Str Ulm, Germany 3/6 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Paracetamolratiopharm 75 mg suppositories, in the Symptomatic treatment of mild to moderate pain and/or fever, is approved. I.1 Problem statement This Decentralised procedure considers a generic version of paracetamol suppositories. The originator products are Ben-u-ron 75 mg / 125 mg suppositories, Authorisation Holder bene Arzneimittel GmbH, Germany. The products were granted marketing authorisations in Germany on With Germany as the Reference Member State in this Procedure, Ratiopharm GmbH is applying for the Marketing Authorisations for Paracetamol-ratiopharm 75 mg in Luxembourg. I.2 About the product Paracetamol is a pharmaceutical well-known substance. Paracetamol is a metabolite of phenacetin. Paracetamol can be given at least orally, rectally or intravenously. Oral dosage forms available include tablets, soluble tablets, extended-release tablets, chewable-tablets and suspensions. Analgesia and antipyresis are the two cardinal pharmacodynamic effects and therefore Paracetamol is used worldwide for the symptomatic treatment of mild to moderately severe pain and fever. It is very well tolerated and safe, and has a definitely positive benefit/risk ratio. Toxic effects are highly dosedependend, and unexpected toxic reactions, such as anaphylaxis or allergic reactions, are extremely rare. Paracetamol has been marketed since At present scientific discussion about hepatic toxicity of paracetamol takes place. Subsequent to serious discussion about the hepatoxic potential of paracetamol (Brune, K. Lebertoxizität von Paracetamol Internist 2007, ), the SmPC and PL have been substantially adapted (revisions in sections 4.2, 4.3, 4.4 and 4.8 were made) during the last renewal procedure of the originator product (DE/H/0394/001/R/002). Nevertheless the benefit-risk ratio of paracetamol 75 mg suppositories remains positive. I.3 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. II. II.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The active substance paracetamol is described in the current European Pharmacopoeia. The quality of paracetamol, sourced from the manufacturer, is controlled in compliance with the corresponding monograph of the European Pharmacopoeia. The suitability of the monograph to test 4/6 Public AR

5 the drug substance has been verified by EDQM, resulting in granting a certificate of suitability to the active substance manufacturer. The re-test period was not subject of the evaluation conducted by EDQM and therefore not mentioned in the CEP. On the basis of submitted stability data, the proposed re-test period of 5 years can be accepted. Drug product The development of the product has been described, the choice of excipients is justified and their functions explained. Relevant quality characteristics of the drug substance and the drug product are specified. The proposed limits are in general accepted. The ingredients and the manufacturing process of the drug product are considered to be suitable to produce the proposed suppositories of appropriate quality. Descriptions of the analytical methods used to analyse the drug substance and drug product are adequate, the validation results are plausible. Batch analytical results show that the finished product meets the proposed acceptance criteria. On the basis of submitted real time stability data after 12 month storage at 25 C ± 2 C / 60% ± 5% rel. humidity and taking into account the possibility of extrapolation of data according to Annex II of the Guideline on Stability Testing (CPMP/QWP/122/02 Rev. 1 corr),a shelf-life of 18 months with the storage instruction Do not store above 25 C is accepted for the finished product. II.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol are well known. As paracetamol is a widely used, well-known active substance, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. There are no toxicological issues concerning the impurity profile or the excipients used in Paracetamol-ratiopharm 75 mg suppositories. Nonclinical relevant sections of the SmPC and PL were amended as indicated and considered to be satisfactory. II.3 Clinical aspects The to-be-marketed-formulation is a suppository containing 75 mg paracetamol. The application is based on Directive 2001/83/EC Article 10a, well-established-use application. Therefore to support the application, the applicant refers to public literature. No clinical trials or bioequivalence studies have been conducted. The efficacy / safety ratio of this product is positive. The proposed SPC and PIL has been adopted to the newest SPC and PL of the originator product benu-ron 75 mg Suppositories, dated on User Testing Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). Both the first and the second test round met the success criteria of 90% of the subjects being able to locate the requested information, and of those, 90% being able to give the correct answer, to indicate that they understood the information presented. In conclusion, the user test is considered acceptable. 5/6 Public AR

6 The user testing for the parent PL was performed by undertaking direct personal interviews by PRIME AD! PROJECTS GmbH in The overall result of this readability test performed with mock-ups of the package leaflet (German version) for Partacetamol-ratiopharm 500 mg effervescent tablets, is in compliance with the general acceptance criteria stipulated in the Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use. It demonstrates that potential users are able to locate and understand the information given in the package leaflet. Pharmacovigilance system Description of Pharmacovigilance System Details have been provided of the Teva pharmacovigilance system (Version 9 dated June 2010). 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. Risk Management Plan N/A III. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data. No clinical trials or bioequivalence studies have been conducted. The application is approved. 6/6 Public AR