Public Assessment Report. Scientific discussion. Paracetamol Orifarm 500 mg film-coated tablets. (Paracetamol) DK/H/2271/001/DC.

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1 Public Assessment Report Scientific discussion Paracetamol Orifarm 500 mg film-coated tablets (Paracetamol) DK/H/2271/001/DC 15 October 2014 This module reflects the scientific discussion for the approval of Paracetamol Orifarm. The procedure was finalised on 20 November For information on changes after this date please refer to the module Update.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Paracetamol Orifarm 500 mg film-coated tablets, from Orifarm Generics A/S. The product is indicated for: Symptomatic treatment of mild to moderate pain and fever. A comprehensive description of the indications and posology is given in the SmPC. Paracetamol is a mild analgesic and antipyretic. It is very widely used throughout the world for the shortterm treatment of mild to moderate pain. This decentralised procedure concerns a generic application claiming essential similarity with the reference product Panodil 500 mg film-coated tablets which has been registered in Denmark by GlaxoSmithKline Consumer Healthcare A/S since The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. II. QUALITY ASPECTS II.1 Each film-coated tablet contains 500 mg of paracetamol. The tablets are white to off-white coloured film-coated tablets 17 x 7.2 mm debossed with PARA500 on one side and score line on the other side. The tablets can be divided into equal doses. The tablets are packed in blisters (PVC/Aluminium) in pack sizes of 10, 20, 30, 50 and 100 film-coated tablets and in bottles (HDPE) with screw caps (PP or PE) in pack-sizes of 50, 100, 200, 300, 400, 500 and 1000 film-coated tablets. However, not all pack sizes may be marketed. The excipients in the tablet core are: Starch, pregelatinized; Povidone; Sodium starch glycolate and Stearic acid. The film-coating consists of: Hypromellose and Macrogol. The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance The active substance paracetamol is described in the European Pharmacopoeia. It is a white to almost white crystalline powder. It is sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. It is not optically active. The manufacturer of the active substance has obtained a Certificate of Suitability, which is valid. The MAH s active substance specification includes all tests of the CEP. The re-test period is according to the CEP. 2/5

3 II.3 Medicinal Product The drug product proposed for marketing is a film-coated tablet. The development of the product has been described, the choice of excipients is justified and their functions explained. The manufacturing process is a standard process and the content of the active substance in the tablet is high. The active substance dissolves more than 85% in 15 minutes in all dissolution media. Exemption from the need to demonstrate in-vivo bioequivalence (perform bioequivalence studies) is claimed on the basis of dissolution studies (BCS biowaiver). The drug product specification is based on the BP monograph on paracetamol tablets. The pilot-scale batches comply with the specification except regarding appearance of the tablets. A different debossing and inclusion of a tablet score are proposed for commercial scale batches. The process validation protocol includes an evaluation/test for subdivision of scored tablets and this is considered acceptable considering the MAH is obliged to inform the competent authorities if any unexpected results are seen during process validation. It is proposed to market the drug product in two types of blisters and in a HDPE container with PE or PP caps. The proposed shelf-life of 30 months is accepted based on 18 months of stability data. A proposed bulk holding time of 12 months is acceptable based on real time data. A photostability study confirms the finished product is not sensitive to light exposure. III. NON-CLINICAL ASPECTS III.1 Pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol are well known. As paracetamol is a widely used, well-known active substance, the MAH has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The non-clinical overview report refers 24 publications up to year The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. III.2 Ecotoxicity/environmental risk assessment (ERA) Since Paracetamol Orifarm is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. IV. CLINICAL ASPECTS IV.1 Paracetamol is a well-known active substance with established efficacy and tolerability. As paracetamol is a widely used, well-known active substances, the MAH has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The clinical overview report refers 21 publications up to year The clinical overview on the clinical pharmacology, efficacy and safety is adequate. 3/5

4 Paracetamol is considered a BCS class I substance with high solubility and complete absorption. Therefore comparative in-vitro dissolution is sufficient to establish bioequivalence and no in-vivo bioequivalence studies are needed to show essential similarity. Paracetamol Orifarm 500 mg film-coated tablets are intended for oral use only. No absorptionmodifying agents are included in the formulation. No special issues related to bioavailability that might affect efficacy and/or the safety of the product are present. Comparative dissolution profiles in water and at ph 1.2, 4.5 and 6.8 shows that Paracetamol Orifarm 500 mg film-coated tablets and the reference product Panodil (from Denmark) has comparable dissolution profiles and can be regarded as bioequivalent. IV.2 Risk Management Plan 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 Paracetamol Orifarm. Routine Pharmacovigilance is used for the safety concerns overdose. The Summary of Product Characteristics (SmPC) include information regarding the risk of overdose, which contributes towards reducing the risk. Warnings in sections 4.2, 4.4, 4.8, 4.9 of the SmPC. The Patient information Leaflet (PIL) likewise includes information regarding the risk of overdose, which contributes towards reducing the risk. This medicine has no additional risk minimisation measures. Summary table of safety concerns as approved in RMP Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP V. 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 Paracetamol Orifarm 500 mg tablets (nationally approved in Denmark). The bridging report submitted by the MAH has been found acceptable. 4/5

5 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Paracetamol Orifarm 500 mg film-coated tablets has a proven chemical-pharmaceutical quality and is a generic form of Panodil. Panodil is a well-known medicinal product with an established favourable efficacy and safety profile. Paracetamol is considered a BCS class I substance with high solubility and complete absorption. Therefore comparative in-vitro dissolution is sufficient to establish bioequivalence and no in-vivo bioequivalence studies are needed to show essential similarity. 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 Paracetamol Orifarm. Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that essential similarity has been demonstrated for Paracetamol Orifarm with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised on 20 November Paracetamol Orifarm was authorised in Denmark on 18 December According to the List of Union reference dates and frequency of submission of periodic safety update reports (PSURs), no PSURs are required for this product. The date for the first renewal will be: 20 November There were no post-approval commitments made during the procedure. 5/5