Public Assessment Report. Decentralised Procedure

Public Assessment Report Decentralised Procedure PERRIGO PARACETAMOL/GUAIFENESIN/PHENYLEPHRINE HYDROCHLORIDE 500 MG/200 MG/10 MG POWDER FOR ORAL SOLUTION UK Licence No: PL 12063/0118 WRAFTON LABORATORIES LIMITED

LAY SUMMARY On 19 th September 2012, the UK granted Wrafton Laboratories Limited a Marketing Authorisation (licence) for Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution. Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution contains: Paracetamol which is a pain reliever (analgesic) and helps reduce your temperature when you have a fever. Guaifenesin which is an expectorant to help loosen phlegm. Phenylephrine which is a decongestant to reduce swelling in the passages of the nose to help you breathe more easily. Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution is used for the short term symptomatic relief of colds and flu including aches and pains, headache, blocked nose and sore throat, chills and fever, and for relief from chesty coughs. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution outweigh the risks; hence a Marketing Authorisation has been granted. 2

TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 5 Module 4: Labelling Page 6 Module 5: Scientific Discussion Page 10 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Page 19 3

Module 1 Product Name Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution Type of Application Generic hybrid, Article 10.3 Active Substance Form Strength Marketing Authorisation Holder (MAH) Reference Member State (RMS) Concerned Member State (CMS) Procedure Number Paracetamol Guaifenesin Phenylephrine hydrochloride Powder for oral solution 500 mg Paracetamol 200 mg Guaifenesin 10 mg Phenylephrine hydrochloride Wrafton Laboratories Limited, trading as Perrigo Braunton Devon EX33 2DL United Kingdom United Kingdom (UK) The Czech Republic (CZ), Germany (DE), Hungary (HU), Italy (IT) and Poland (PL) End of Procedure Day 210: 1 st August 2012 4

Modules 2 and 3 Summary of Product Characteristics and Patient Information Leaflet In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. 5

Module 4 Labelling 6

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Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Czech Republic, Germany, Hungary, Italy, Poland and the UK considered that the application for Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution could be approved. This product has a general sales licence (GSL) and is indicated for the short term symptomatic relief of colds and flu including aches and pains, headache, blocked nose and sore throat, chills and fever, and for relief from chesty coughs. This application for Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution is submitted as an abridged application according to Article 10(3) of Directive 2001/83/EC, claiming to be a hybrid medicinal product to Beechams All-in-One Liquid (500 mg paracetamol, 200 mg guaifenesin and 10 mg phenylephrine hydrochloride per 5 ml), authorised in the UK to Beechams Group PLC on 19 th October 1994 (PL 00079/0320). Paracetamol [acetaminophen; N-(4-Hydroxyphenyl) acetamide] is a para-aminophenol derivative with analgesic, antipyretic and weak anti-inflammatory properties. It is rapidly absorbed and its pharmacokinetic properties have been extensively studied. Studies confirm the analgesic, antipyretic/anti-inflammatory effects of paracetamol and guaifenesin and phenylephrine hydrochloride are administered in fixed-combination products of this type for their additional pharmacodynamic contribution. Guaifenesin is a well-established constituent in over-the-counter expectorants. Although its mechanism of action is poorly understood, it reduces cough reflex sensitivity as well as aiding the expulsion of respiratory mucus associated with upper respiratory tracts infections. It is rapidly absorbed and its pharmacokinetcs are well established. Phenylephrine is a selective α-adrenergic sympathomimetic and at therapeutic doses has negligible effect on β receptors or of the central nervous system (CNS). It is rapidly absorbed and has a well understood pharmacokinetic profile. No new non-clinical studies were conducted, which is acceptable given that the product contains widely-used, well-known drug substances. No clinical studies have been performed and none are required for this application as the pharmacology of paracetamol, guaifenesin and phenylephrine hydrochloride is well-established. 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. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, close-out letters or exchange of information issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-community sites. 10

II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the drug substance (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form and strength Reference numbers for the Decentralised Procedure Reference Member State Member States concerned Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution Paracetamol Guaifenesin Phenylephrine hydrochloride Paracetamol combinations excl. psycholeptics (N02BE51) Powder for oral solution 500 mg Paracetamol 200 mg Guaifenesin 10 mg Phenylephrine hydrochloride United Kingdom The Czech Republic (CZ), Germany (DE), Hungary (HU), Italy (IT) and Poland (PL) Marketing Authorisation Number PL 12063/0118 Name and address of the authorisation holder Wrafton Laboratories Limited, trading as Perrigo Braunton Devon EX33 2DL United Kingdom 11

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Drug substance Paracetamol INN/Ph.Eur name: Chemical name: Paracetamol N-(4-Hydroxyphenyl) acetamide Structural formula: Molecular formula: C 8 H 9 NO 2 Molecular weight: 151.2 Appearance: Solubility: Guaifenesin INN/Ph.Eur name: Chemical name: A white, or almost white, crystalline powder Sparingly soluble in water, freely soluble in alcohol and very slightly soluble in methylene chloride. Guaifenesin (2RS) - 3(2-methoxyphenoxy) propane-1,2-diol Structural formula: Molecular formula: C 10 H 14 O 4 Molecular weight: 198.22 Appearance: Solubility: A white, or almost white, crystalline powder Sparingly soluble in water and soluble in alcohol. 12

Phenylephrine hydrochloride INN/Ph.Eur name: Phenylephrine hydrochloride Chemical name: (1R)-1-(3-Hydroxyphenyl)-2-(methylamino) ethanol hydrochloride Structural formula: Molecular formula: C 9 H 14 ClNO 2 Molecular weight: 203.7 Appearance: Solubility: A white, or almost white, crystalline powder Freely soluble in water and soluble in alcohol. The sources of paracetamol, guaifenesin and phenylephrine hydrochloride comply with the relevant European Pharmacopoeia monographs for paracetamol, guaifenesin and phenylephrine hydrochloride, respectively. The manufacturers of the drug substances hold valid EDQM (European Directorate for the Quality of Medicines and Healthcare) Certificates of Suitability. The quality of the substances is suitably controlled in line with the current edition of the relevant European Pharmacopoeia Monographs. The manufacturing process, control of materials, control of critical steps, validation and process development for paracetamol, guaifenesin and phenylephrine hydrochloride were assessed and approved by the EDQM in relation to the granting of the Certificates of Suitability and are therefore satisfactory. Appropriate specifications with suitable test methods and limits are provided for the drug substances. The methods of testing and limits for impurities and residual solvents for each drug substance are in compliance with current guidelines. Batch analysis data for each drug substance are provided and comply with the proposed specifications. The container closure system and re-test period for paracetamol, guaifenesin and phenylephrine hydrochloride complies with the container closure and re-test period specified on the relevant Certificates of Suitability. 13

P. Medicinal Product Other Ingredients Other ingredients consist of pharmaceutical excipients sucrose, citric acid E330, tartaric acid E334, sodium cyclamate E952, sodium citrate E331, acesulfame potassium E950, aspartame E951, powdered menthol flavour, lemon flavour, lemon juice flavour and quinoline yellow E104. With the exception of powdered menthol flavour, lemon flavour, lemon juice flavour and quinoline yellow E104; all excipients comply with their respective European Pharmacopoeia monographs. Powdered menthol flavour, lemon flavour, lemon juice flavour and quinoline yellow E104 all comply with in-house specifications. None of the excipients used contain material of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to produce a safe, efficacious product which would be a dry powder mixture that can be easily and rapidly reconstituted with water containing paracetamol, guaifenesin and phenylephrine hydrochloride that could be considered a hybrid product to Beechams All-in-One Liquid. The quantity of the drug substances is such that one sachet corresponds to 20ml oral solution. The formulation of the finished product was based on the formulation of Max Strength Cold and Flu Relief Sachets, authorised to Wrafton Laboratories Limited on 19 th September 2003 (PL 12063/0034). The applicant has provided a suitable product development section. Valid justifications for the use and amounts of each excipient have been provided. Satisfactory dissolution stability data have been provided. A commitment has been provided to reformulate the product and reduce the amount of the sweetener cyclamate to levels in line with those recommended by the Commission on Dietary Food Additive Intake in the European Union COM(2001) 542. 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 and has shown satisfactory results. Process validation data on commercial-scale batches have been provided and are satisfactory. Finished Product Specification The finished product specification proposed for the product is acceptable. Test methods have been described and have been 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 This product is packaged in sachets composed of: i) Low density polyethylene 30 gm -2, aluminium foil 15 micron, low density polyethylene 12 gm -2 and paper 40 gm -2 (outer layer). ii) Surlyn 25 gm -2 (product contact layer a thermoplastic sheet/film)/aluminium foil 15 microns/low density polyethylene 12 gm -2 / paper 40-45 gm -2 (outer layer). 14

Pack sizes are 5 and 10 sachets. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary product packaging complies with the relevant EU directives and EU legislation regarding contact with food and pharmaceutical use. Stability of the product Stability studies were performed on batches of the finished product in the packaging proposed for marketing and in accordance with current guidelines. These data support a shelf-life of 36 months for the product as packaged and a shelf-life of 1½ hours after reconstitution. This medicinal product does not require any special storage conditions. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically acceptable. The UK approved labelling (text only) are included in module 4 of this report. The requirements (Article 59(3) of Directive 2001/83/EC as amended) for user testing have been adequately met by means of a bridging report to a similar PIL of an already approved product (parent product Multi-action Cough & Cold Capsules, containing the same active ingredients and with comparable leaflet format, layout and style). MAA form The MAA form is pharmaceutically satisfactory. Pharmaceutical Expert Report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion From a quality point of view, it is recommended that a Marketing Autorisation is granted for this application. 15

III.2 NON-CLINICAL ASPECTS The pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol, guaifenesin and phenylephrine hydrochloride are well-known. As paracetamol, guaifenesin and phenylephrine hydrochloride are widely used, well-known drug substances, the applicant has not provided any additional studies and none are required. An overview based on literature is therefore appropriate. Non-Clinical Overview The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. Impurities The impurities identified in the drug substance and drug product comply with the levels specified in the European Pharmacopoeia and the limits specified by the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) guidelines. Environmental Risk Assessment A satisfactory justification has been provided for the absence of an Environmental Risk Assessment. Conclusion From a non-clinical point of view, it is recommended that a Marketing Authorisation is granted for this application. 16

III.3 CLINICAL ASPECTS Clinical Pharmacology No new pharmacokinetic or pharmacodynamic data were submitted with this application and none were required. The proposed product is a hybrid product of the reference product; a powder for oral solution which has the same qualitative and quantitative composition in terms of the drug substances as the reference product, Beechams All-in-One Liquid. Therefore, as per the Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98 Rev 1/Corr**, a bioequivalence study is not required for this application. Efficacy No new efficacy data were submitted with this application and none were required. Safety No new safety data were submitted with this application and none were required. The Pharmacovigilance System and Risk Management Plan The RMS considers that 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. A satisfactory justification has been provided for the absence of a Risk Management Plan. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are clinically satisfactory and consistent with those for the reference product, where appropriate. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. MAA form The MAA form is clinically satisfactory. Conclusion From a clinical point of view, it is recommended that a Marketing Authorisation is granted for this application. 17

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution are well-defined and controlled. The specification and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. CLINICAL The proposed product, Perrigo Paracetamol/Guaifenesin/Phenylephrine hydrochloride 500 mg/200 mg/10 mg powder for oral solution is a hybrid product of Beechams All-in-One Liquid. No new or unexpected safety concerns arise from this application. The SmPC, PIL and labelling are satisfactory and consistent with that for the reference product, where appropriate. RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol, guaifenesin and phenylephrine hydrochloride is considered to have demonstrated the therapeutic value of the compounds. The benefit-risk ratio is, therefore, considered to be positive. 18

Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome 19