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Murine Red & Sore Eyes 0.12mg/ml Eye Drops, solution. UK/H/5327/001/DC

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Public Assessment Report

Decentralised Procedure

Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution

(naphazoline hydrochloride)

Procedure No: UK/H/5327/001/DC

UK Licence No: PL 18259/0009

Prestige Brands (UK) Limited


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LAY SUMMARY Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution

(naphazoline hydrochloride, eye drops solution, 0.12mg/ml) This is a summary of the Public Assessment Report (PAR) for Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution (PL 18259/0009; UK/H/5327/001/DC). It explains how Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution. For practical information about using Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution, patients should read the package leaflet or contact their doctor or pharmacist. The product may be referred to as Murine in this report. What is Murine and what is it used for? Murine contains the active substance, naphazoline hydrochloride, which belongs to the group of medicines called local vasoconstrictors. Murine is used to relieve occasional, minor redness and irritation in eyes, in adults and children aged 12 years and over. This product is for intermittent or occasional use only. Naphazoline hydrochloride has been licensed, in the UK, as an ocular preparation for the proposed indications since 1972. How is Murine used? Murine can be obtained without a prescription, available only from pharmacies under the supervision of a pharmacist. Murine is applied to the eyes. The hands should be washed before use. Touching the dropper on any surface should be avoided. The recommended dose is: 1 or 2 drops gently squeezed into each eye, 2 or 3 times daily. The patient should talk to a doctor if he/she does not feel better or if he/she feels worse after 24 hours. For further information on how Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution is used, please refer to the Summary of Product Characteristics and the Patient Information Leaflet available on the MHRA website. How does Murine work? The active substance, naphazoline hydrochloride, acts by narrowing the blood vessels in the eye, thereby reducing redness and swelling. Murine starts working within 1 minute and lasts for 3 hours.


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How has Murine been studied? As naphazoline hydrochloride is a well-known substance, and its use in the relief of occasional, minor redness and irritation in eyes, in adults and children aged 12 years and over is well established, the applicant (Prestige Brands [UK] Limited) presented data from the scientific literature. The literature provided confirmed the efficacy and safety of naphazoline hydrochloride in the relief of occasional, minor redness and irritation in eyes, in adults and children aged 12 years and over. What are the risks of Murine? Like all medicines, this medicine can cause side effects, although not everybody gets them. For information about side effects that may occur with using Murine, please refer to the package leaflet or the Summary of Product Characteristics available on the MHRA website. Why is Murine approved? The use of Murine in the relief of occasional, minor redness and irritation in eyes in adults and children over 12 years old is well-established in medical practice and documented in the scientific literature. No new or unexpected safety concerns arose from this application. It was, therefore, considered that the benefits of Murine outweigh the risks and the grant of a Marketing Authorisation was recommended. What measures are being taken to ensure the safe and effective use of Murine? A Risk Management Plan has been developed to ensure that Murine is used as safely as possible. Based on this plan, safety information has been included in the Summary of Product Characteristics and the package leaflet for Murine, including the appropriate precautions to be followed by healthcare professionals and patients. Other information about Murine. A Marketing Authorisation was granted in the UK on 15 May 2014. The full PAR for Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution follows this summary. For more information about treatment with Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in July 2014.


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TABLE OF CONTENTS

Module 1: Information about the initial procedure Page 5 Module 2: Summary of Product Characteristics Page 6 Module 3: Patient Information Leaflet Page 7 Module 4: Labelling Page 8 Module 5: Scientific discussion during the initial procedure Page 11 I Introduction II About the product III Scientific overview and discussion III.1 Quality aspects III.2 Non-clinical aspects III.3 Clinical aspects IV Overall conclusion and benefit/risk assessment Module 6: Steps taken after the initial procedure Page 16


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Module 1 Information about the initial procedure

Product Name Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution Type of Application Well-established use, Article 10a Active Substance Naphazoline hydrochloride Form Eye drops, solution Strength 0.12 mg/ml naphazoline hydrochloride MA Holder

Prestige Brands (UK) Limited 57 High Street Yatton Somerset BS49 4EQ United Kingdom

Reference Member State (RMS) UK Concerned Member States (CMS) Denmark, Finland, Norway and Sweden Procedure Number UK/H/5327/001/DC Timetable Day 210 – 16 April 2014


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Module 2 Summary of Product Characteristics

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 3 Patient Information Leaflet

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.

Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution UK/H/5327/001/DC

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Module 4 Labelling


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Module 5 Scientific discussion during the initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution (PL 18259/0009; UK/H/5327/001/DC) could be approved. The product is a pharmacy (P) medicine, available from pharmacies. Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution is indicated, in adults and children aged 12 years and over, for the relief of occasional, minor redness and irritation of the eye. This application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Denmark, Finland, Norway and Sweden as Concerned Member States (CMS). The application was submitted under Article 10a of Directive 2001/83/EC, as amended, claiming to be an application for a product containing an active substance of well-established use. Naphazoline hydrochloride has been licensed, in the UK, as an ocular preparation for the proposed indications since 1972. The active ingredient, naphazoline hydrochloride, is an imidazoline derivative sympathomimetic agent and is widely used as an ocular or nasal decongestant. Naphazoline hydrochloride is a well-established vasoconstrictor which acts on alpha adrenergic receptors in the arterioles of the conjunctiva. When applied to mucous membranes naphazoline hydrochloride causes vasoconstriction, which results in a rapid and prolonged action of reduced swelling and conjunctival congestion. Bibliographic literature data on naphazoline hydrochloride have been submitted to support this application. No new non-clinical or clinical studies were conducted for this application, which is acceptable given that this is a bibliographic application for a product containing an active ingredient of well-established use. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release of this product. The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 16 April 2014. After a subsequent national phase, a licence was granted in the UK on 15 May 2014.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution

Name of the active substance (INN) Naphazoline hydrochloride Pharmacotherapeutic classification (ATC code)

Sympathomimetics used as decongestants (ATC code: S01GA01)

Pharmaceutical form and strength Eye drops, solution; 0.12 mg/ml naphazoline hydrochloride

Reference number for the Decentralised Procedure

UK/H/5327/001/DC

Reference Member State (RMS) United Kingdom Concerned Member States (CMS) Denmark, Finland, Norway and Sweden Marketing Authorisation Number PL 18259/0009 Name and address of the authorisation holder

Prestige Brands (UK) Limited 57 High Street Yatton Somerset BS49 4EQ United Kingdom

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS ACTIVE SUBSTANCE INN: Naphazoline hydrochloride Chemical name: 2-(Naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole hydrochloride. Structural formula:

Molecular formula: C14H15ClN2 Molecular Weight: 246.7 Appearance: White or almost white crystalline powder. Solubility Freely soluble in water and soluble in ethanol (96%). Naphazoline hydrochloride is the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been described adequately and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Appropriate proof-of-structure data have been supplied. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance. Analytical methods have been validated appropriately and are satisfactory for ensuring compliance with the relevant specifications. Batch analysis data are provided that comply with the proposed specification. Satisfactory Certificates of Analysis have been provided for all working standards. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuff.


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Appropriate stability data have been generated to support a suitable retest period when stored in the proposed packaging. MEDICINAL PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients benzalkonium chloride solution, boric acid (E284), borax (E285), purified water and disodium edetate. Appropriate justifications for the inclusion of each excipient have been provided. All excipients comply with their respective European Pharmacopoeia monographs. Certificates of Analysis are provided for each excipient showing compliance with their respective monographs. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programme was to formulate a robust stable ophthalmic preparation containing 0.12 mg/ml naphazoline hydrochloride. Suitable pharmaceutical development data have been provided for this application. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, together with an appropriate account of the manufacturing process. The manufacturing process has been validated using production-scale batches and has shown satisfactory results. Control of Finished Product The finished product specification proposed for the product is acceptable. Test methods have been described that have been adequately validated, as appropriate. Batch data have been provided that 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 opaque high-density polyethylene (HDPE) bottles with low-density polyethylene (LDPE) plastic plugs and polypropylene plastic caps, containing 5 ml or 10 ml of solution. The product is packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons, in a pack size of 1 × 5 ml and 1 x 10 ml bottles. Satisfactory specifications and Certificates of Analysis for all packaging materials have been provided. All primary packaging complies with current European regulations concerning plastic immediate packaging materials. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of the finished product in the packaging proposed for marketing. Based on the results, shelf-lives of 2 years for the unopened 5ml pack size and 3 years for unopened 10 ml pack size have been set. The product should be discarded four weeks after first opening. The storage instructions for the product are “Do not store above 25°C. Do not refrigerate or freeze.” Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product.


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Bioequivalence/Bioavailability A bioequivalence study was not necessary to support this type of application. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labels are satisfactory from a pharmaceutical perspective. A package 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 the patients/users are able to act upon the information that the leaflet contains. Marketing Authorisation Application (MAA) form The MAA form is satisfactory. Expert report (Quality Overall Summary) The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended. III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of naphazoline hydrochloride are well-known, no new non-clinical data have been submitted and none are required. The applicant’s non-clinical overview has been written by appropriately qualified persons and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. The Marketing Authorisation Holder has submitted an acceptable Environmental Risk Assessment, prepared in accordance with the “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use” (EMEA/CHMP/SWP/4447/00). In the Phase I study, the exposure of the environment was evaluated. The predicted environmental concentration (PEC) in surface water for naphazoline hydrochloride was calculated as less than 0.01microgram/L, which is the PEC action limit. In addition, the calculated octanol/water coefficient (Log Kow) was less than the action limit of 4.5. Hence, the results of the Phase I study, indicates that the therapeutic use of Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution is unlikely to pose a risk to the environment following prescribed usage. The grant of a Marketing Authorisation is recommended. III.3 CLINICAL ASPECTS No new clinical pharmacology data have been submitted and none are required for this type of application. The clinical pharmacology of naphazoline hydrochloride is well-known. Efficacy No new efficacy data have been submitted and none are required this type of application. The clinical efficacy of naphazoline hydrochloride is well-established. Efficacy is adequately reviewed in the clinical overview Safety No new safety data were supplied or required for this bibliographic application. Safety is adequately reviewed in the clinical overview. The safety profile of naphazoline hydrochloride is well-known.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are satisfactory from a clinical perspective. The SmPC is consistent with that for the originator product. The PIL is consistent with the details in the SmPC and in line with the current guidance. The labelling is in line with the current guidance. 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. 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 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. An acceptable Risk Management Plan for the product has been submitted. Conclusion The grant of a Marketing Authorisation is recommended. IV OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Murine Red & Sore Eyes 0.12mg/ml Eye Drops, Solution 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 on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology of naphazoline hydrochloride are well-known, no additional data were required. EFFICACY No new clinical data were submitted and none were required for this type of application. The published literature supports the efficacy of this product in the proposed indications. The efficacy of naphazoline hydrochloride is well-known. The presented evidence for well-established use of the active substance is sufficient. SAFETY The safety profile of naphazoline hydrochloride is well-known. No new safety data were submitted and none were required for this application. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and in line with current guidance. 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 naphazoline hydrochloride is considered to have demonstrated the therapeutic value of the product. The benefit/risk balance is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER THE INITIAL PROCEDURE - SUMMARY

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