Decentralised Procedure

Public Assessment Report

Visine Yxin Hydro 0,5 mg/ml Augentropfen, Lösung

Tetryzoline hydrochloride

DE/H/5718/001/DC

Applicant: Johnson & Johnson Consumer Services EAME Ltd.

Date: 10th March 2021

This module reflects the scientific discussion for the approval of the above-mentioned product. The procedure was finalised on 18th November 2020.

TABLE OF CONTENTS

I INTRODUCTION ...... 4 II EXECUTIVE SUMMARY ...... 4 II.1 PROBLEM STATEMENT...... 4 N/A ...... 4 II.2 ABOUT THE PRODUCT ...... 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER ...... 5 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES...... 6 III SCIENTIFIC OVERVIEW AND DISCUSSION ...... 6 III.1 QUALITY ASPECTS ...... 6 III.2 NON CLINICAL ASPECTS ...... 7 III.3 CLINICAL ASPECTS ...... 7 IV BENEFIT RISK ASSESSMENT ...... 11

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ADMINISTRATIVE INFORMATION Proposed name of the medicinal Visine Yxin Hydro 0,5 mg/ml Augentropfen, Lösung product in the RMS Name of the drug substance (INN Tetryzoline hydrochloride name): Pharmaco-therapeutic group S01GA02 (ATC Code): Pharmaceutical form(s) and Eye drops, solution; 0,5 mg/ml strength(s): Reference Number(s) for the DE/H/5717/001/DC withdrawn on 08.11.2019 Decentralised Procedure DE/H/5718/001/DC Reference Member State: DE Concerned Member States: BG, CY, CZ, EE, EL, ES, HR, HU, LT, LV, PL, PT, RO, SI, SK Legal basis of application: Article 10(3) hybrid application Applicant (name and address) Johnson & Johnson Consumer Services EAME Ltd. Foundation Park, Roxborough way SL6 3UG Maidenhead, United Kingdom

Names and addresses of all proposed Janssen Pharmaceutica NV manufacturer(s) responsible for Turnhoutseweg 30, 2340 Beerse, Belgium batch release in the EEA

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I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for “Visine Yxin Hydro 120,5 mg/ml Augentropfen, Lösung” with the following indication:

Temporary relief of hyperemia of the eye secondary to non-infectious eye irritations e.g. due to smoke, dust, wind, chlorinated water, light or allergic conjunctivitis. is approved.

Please note that due to withdrawal of the DC Procedure No: DE/H/5717/001/DC from 08.11.2019 the DC Procedure is closed.

II EXECUTIVE SUMMARY II.1 Problem statement N/A

II.2 About the product Tetryzoline hydrochloride (synonymous: tetrahydrozoline hydrochloride) is an OTC , topical, ophthalmic vasoconstrictor widely used for the symptomatic relief of minor ocular irritation of various etiologies.

Mode of action Tetryzoline is a sympathomimetic agent belonging to the imidazoline group of decongestants. It directly stimulates the alpha-adrenergic receptors of the sympathetic nervous system with little to no effect on beta-adrenergic receptors. The drug reduces hyperemia by local stimulation of conjunctival α- receptors leading to vasoconstriction of blood vessels. Conjunctival vasodilation and edema resolve, subsequently resulting in re-whitening of the eye and relief of symptoms of ocular irritation.

Pharmacological classification Pharmacotherapeutic category: decongestants and antiallergics, sympathomimetics used as decongestants. ATC code: S01GA02. The formulation contains Tetryzoline Hydrochloride as the active ingredient, Polyquaternium-42 (PQ-42) as preservative, Boric Acid, Borax, Disodium Phosphate Anhydrous, Sodium Citrate dihydrate are used for the maintenance of buffer system.

The Visine Yxin Hydro (Tetryzoline HCl 0.05% Ophthalmic Solution) has been developed in order to replacing BAK with Polyquaternium-42 (PQ-42). The drug product is intended for ocular use and the pharmaceutical form is clear solution. The Visine Yxin Hydro (Tetryzoline HCl 0.05% Ophthalmic Solution) is multi-dose bottle with a preservative agent.

Therapeutic indication There were minor differences in the wording of the indications between the countries, although they are all for relief of hyperemia. The proposed indication covered these indications. The proposed indication of Visine Yxin Hydro containing 0.05% tetryzoline is:

“For temporary relief of hyperemia of the eye secondary to non-infectious eye irritations e.g. due to smoke, dust, wind, chlorinated water, light or allergic conjunctivitis.”

This indication is consistent with that in the reference SPCs and is supported by the provided clinical data.

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Posology Adults, adolescents and children aged 6 years and older: The dose is 1-2 drops into the affected eye(s) 2 to 3 times per day. This medicinal product should be used for the shortest time necessary to relieve symptoms. See section 4.4 for risk of rebound in case of prolonged use.

Paediatric population Adult supervision is recommended for use in children under the age of 12 years. Children over 2 and below 6 years: this medicinal product can be administered to children under 6 years of age only following advice from a healthcare professional (see section 4.4).The recommended dose is 1 drop into the affected eye(s) 2 to 3 times per day.

This medicinal product is contraindicated in children under 2 years (see section 4.3).

II.3 General comments on the submitted dossier The submitted dossier supports an application made according to Article 10(3) of Directive 2001/83/EC Hybrid application for Visine Comfort 0,5 mg/ml eye drops and Visine Yxin Hydro 0,5 mg/ml eye drops containing the ocular decongestant tetryzoline hydrochloride 0.05% (0.5mg/ml), for temporary relief of hyperaemia of the eye secondary to non-infectious eye irritations. Based on CMDh Questions & Answers Generic applications (CMDh/272/2012, Rev.3 / Question 11), applications for marketing authorisation for generic and reformulated products for local use should be submitted according to Art. 10.3 of Directive 2001/83/EC and is applicable in case of application in accordance with article 10 (see section 5.3.1.2 of the Notice to applicant volume 2A https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/vol2a_chap1_en.pdf).

Since tetryzoline is an approved over-the-counter ocular decongestant that has been marketed for, more than 60 years, its efficacy and safety is well documented. The dossier for this new formulation of tetryzoline hydrochloride 0.5 mg/mL eye drops, solution is submitted as a ‘hybrid’ application. The EU reference product is Visine Yxin, Augentropfen, Johnson & Johnson GmbH, MA-No.: 6341712.00.00 (DE), MA- Date: 04.05.2005. Both new formulas differ by the nature of their excipients and their speed of action (see section 5.1 of the SmPC). The new formulations compared to the reference product combine the same quantity of active ingredient (tetryzoline hydrochloride 0.5 mg/ml) with different excipients, e.g. the preservative benzalkonium chloride (BAK) is replaced with polyquaternium-42 (PQ-42).

A bioequivalence study is not being possible due to the topical route of administration of this ophthalmic drug, a clinical study to demonstrate therapeutic equivalence to the reference product was conducted in line with the above quoted CMDh recommendations.

The clinical efficacy and safety of tetryzoline 0.05% eye drops are supported by the reference product, Visine® Yxin (German licence number 6341712.00.00), and a review of company-sponsored and published studies. A comprehensive literature search has been performed to identify all relevant references regarding the clinical pharmacology, efficacy and safety of tetryzoline used as a topical ophthalmologic drug.

The therapeutic equivalence study also generated data on onset of symptomatic relief and sensory benefits of the new formulations, which the Company proposes to include in the Summary of Product characteristics, as discussed with BfArM in the written Scientific Advice concluded on 12th March 2018.

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II.4 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.

GMP active substance Regarding the statement on GMP for the active substance, a statement/declaration is provided from the manufacturer responsible for manufacture of the finished product and batch release situated in the EU.

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The active substance is Tetryzoline Hydrochloride, which is described in the Ph. Eur. The ASMF procedure is followed for the drug substance.

The structure of the drug substance has been adequately proven and its physio-chemical properties are sufficiently described.

The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents.

The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated.

Stability studies confirm the retest period.

Conclusion on the ASMF from the proposed API manufacturer: The ASMF is of sufficient quality.

Drug Product The proposed drug product is an eye drop solution containing 0.5 mg/ml of the drug substance Tetryzolin HCl. The solution is filled in 15 ml LDPE bottles with a LDPE dropper tip and a child resistant screw cap. The drug product is a multi dose preparations and the formulations contain a preservative. As preservative Polyquaternium-42 (Polixetonium chloride) is used. The quality of the excipients complies with the requirements of the respective Ph. Eur. Monograph where applicable. Polyquaternium-42 (Polixetonium chloride) is tested according to an in-house specification. The development of the applied product has been described. The manufacturing process has been sufficiently described and critical steps identified. The product specifications cover relevant parameters for this dosage form. Validation results of the analytical methods have been presented. Batch analysis results are provided for the three process validation batches. The specified parameters are met. Stability data of three production size batches covering 24 months are considered appropriate for justification of a shelf life of 24 months when stored below 30°C. In-use stability study results are considered sufficient to justify an in-use shelf-life of 6 weeks.

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Conclusion: The documentation on the drug product complies with present regulatory requirements.

III.2 Non clinical aspects Limited toxicological data for tetrahydrozoline is available in the published literature. However, Tetrahydrozoline is a well established drug for ophthalmic use over more than 60 years. Toxicology data from the literature has been provided separately.

Based on the acute oral LD50 value, tetryzoline is classified as moderately toxic. However, when used as recommended as eye drops little systemic toxicity is anticipated. Nonclinical studies with single administration or repeated application to eyes in a subacute study had no toxic effects identified. Additionally, the local toxicity study showed no difference of the eyes of the experimental group compared to the control group.

There are no preclinical data regarding the genotoxic, carcinogenic or reproductive toxicity potential of tetryzoline. In addition, no adequate and well-controlled studies with administration of tetryzoline in pregnant or breastfeeding women have been performed. It is also unknown whether tetryzoline or its metabolites are excreted in human milk. Therefore, the applicant has included in section 4.6 of the SMPC that the product should not be used during pregnancy or lactation unless the potential benefit of treatment to the mother outweighs the possible risks to the developing fetus or breastfeeding infant.

Conclusion The pharmacodynamic, pharmacokinetic and toxicological properties of tetryzoline hydrochloride are considered established, because tetryzoline hydrochloride is a widely used active substance in ophthalmic practice for more than 60 years. Accordingly, the applicant has not provided additional non-clinical studies and further studies are not required. The non-clinical characteristics of the active substance are also generally reflected in the proposed SmPC. Consequently, there will be no non-clinical objections against marketing authorization of the concerned tetryzoline hydrochloride eye drops.

Environmental Risk Assessment (ERA) Since “Visine Comfort 0,5 mg/ml Augentropfen, Lösung” and “Visine Yxin Hydro 0,5 mg/ml Augentropfen, Lösung” are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.3 Clinical aspects Since tetryzoline is an approved over-the-counter ocular decongestant that has been marketed for more than 60 years, its efficacy and safety are well documented. In the following sections, the data presented are derived from the unpublished clinical studies, published literature, and post-marketing experience. A comprehensive literature search has been performed to identify all relevant references regarding the clinical pharmacology, efficacy and safety of tetryzoline used as a topical ophthalmologic drug.

Pharmacokinetics No pharmacokinetic studies are conducted or required with the product.

Pharmacodynamics No pharmacodynamic studies are conducted or required with the product.

Clinical efficacy One study (Study, Code: CO-161103095739-VCCT 2017) with the German originator in USA (Andover Eye Associates), was conducted with the proposed product in comparison to the originator. Only this study is discussed in the clinical overview:

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Title of the study „A Single Center, Randomized, Controlled Study to Evaluate the Efficacy of Two Investigational OTC Eye Drops in Healthy Adults with Red Eye”:

Study Objectives The objective of this study is to demonstrate the therapeutic equivalence of two investigational, over-the- counter (OTC) products to an existing marketed OTC redness reliever eye drop in healthy adults with red eye.

Study Design 3-arm (Visine Original, Original PQ42, AR PQ42), single center, double-blinded, balanced incomplete randomized block design study. Subjects underwent a 1-day (3 doses over 9 hour’s total) intervention period where each subject was randomly assigned to receive 2 of the 3 test products to apply to the left and right eyes.

Methodology: Eligible subjects complete 2 clinic visits. All subjects had an ocular health and vision exam for inclusion in the study during clinic Visit 1. Eligible subjects had ocular redness assessments using a 5- point redness scale at Baseline (pre-treatment prior to 1st product application), and then 30 seconds, 60 seconds, and 2 minutes following the 1st product application. Subjects also complete ocular comfort assessments for each eye using a scale of 0 to 10 at Baseline (pre-treatment prior to 1st product application) and immediately following the Ocular Redness Assessment completed at 60 seconds after the 1st product application. The first dose was instilled by trained study staff at the clinic. Subjects also completed a questionnaire at Baseline (pre-treatment prior to 1st product application) and immediately following the 2- minute Ocular Redness Assessment. Subjects provided product and written and verbal instructions to apply the test product at home. Subjects will apply test products at home at 4.5 hours (± 30 minutes) and 9 (± 30 minutes) hours after the 1st product application in the clinic. They also completed an Ocular Comfort Assessment and questionnaire at 10 hours (+ 15 minutes) and 12 hours (+ 15 minutes) at home. Subjects will return in approximately 24 ± 1 hour(s) for a final vision exam.

Efficacy Endpoint(s) The efficacy measurements include clinician assessment of redness, using a 5-point scale: 0 – none to 4 – extremely severe, allowing for 0.5 increments, and subject assessment of ocular comfort, using a scale of 0 to 10.

Primary Efficacy Endpoints -Change from baseline in redness at 60 seconds after the first application.

Secondary Efficacy Endpoints -Change from baseline in redness at 30 seconds after the first application. -Change from baseline in redness at 2 minutes after the first application. -Change from baseline in ocular comfort at approximately 60 seconds after the first application. -Change from baseline in ocular comfort at approximately 10hr (+ 15 minutes) after the first application. -Change from baseline in ocular comfort at approximately 12hr (+ 15 minutes) after the first application. -Subject questionnaire frequency tabulations at baseline, approximately 2 minutes, 10 hours (+ 15 minutes), and 12 hours (+ 15 minutes) after first product application.

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Efficacy results Primary Endpoint - For the FDA-recommended, statistically powered, analysis of the primary endpoint the change from baseline in ocular redness at 60 seconds after the initial eye drop application, the 95% CI for the mean difference between Original PQ42 eye drops and Visine Original eye drops was (-0.140, 0.055) and the 95% CI for the mean difference between AR PQ42 eye drops and Visine Original eye drops was (-0.086, 0.107) both 95% CIs were within the prespecified equivalence interval of (-0.22, 0.44).

- For the additional, insufficiently powered, responder analysis of the primary endpoint, the 95% CI for the odds ratio of Original PQ42 and Visine Original was (0.539, 1.411) and the 95% CI for the odds ratio of AR PQ42 and Visine Original was (0.552, 1.368). Neither 95% CI was within the prespecified equivalence interval of (0.80, 1.25).

Secondary Endpoints - At 30 seconds after the initial eye drop application, there was a statistically significant (p=0.009) decrease from baseline in ocular redness score for eyes treated with AR PQ42 eye drops. At 2 minutes after the initial eye drop application, there was a statistically significant (p<0.001) decrease from baseline in ocular redness score for eyes treated with Visine Original, Original PQ42, and AR PQ24 eye drops.

- At 60 seconds, 10 hours, and 12 hours after the initial eye drop application, there was a statistically significant improvement (p<0.001) from baseline in ocular comfort for eyes treated with Visine Original, Original PQ42, and AR PQ24 eye drops.

- Subject questionnaire results indicated there was improvement from baseline in responses concerning most sensory assessments for all treatments and no clinically important differences among treatments in responses at baseline and at 2 minutes, 10 hours, and 12 hours after the first application. For all treatments, the greatest improvement from baseline was for the statement “My eye feels hydrated,” which Continued through 12 hours. At 2 minutes after treatment in all treatment groups, over 70% of subjects strongly or somewhat agreed with the statements “My eye feels hydrated,” “My eye feels refreshed,” My eye appears healthy,” “The appearance of my eye can show how I really feel,” and “The appearance of my eye gives me confidence to approach others.”

- Post-hoc analysis of the change from baseline for five questions obtained at baseline and during follow- up from the subject questionnaire indicated there were statistically significant (p<0.049) improvements from baseline to at least one follow-up time point for all three eye drops for the questions “My eye feels hydrated.”, “My eye appears healthy.” and “My eye appears to sparkle.” There were statistically significant (p<0.044) improvements from baseline to at least one follow-up time point for the Original PQ42 and AR PQ42 eye drops for the question “The appearance of my eye gives me confidence to approach others”. There were statistically significant (p<0.038) improvements from baseline to at least one follow-up time point for the AR PQ42 eye drops for the question “The appearance of my eye can show how I really feel”.

Efficacy Conclusions This study demonstrated that the investigational product provided statistically powered therapeutically equivalent redness relief compared with the reference product Visine Original eye drops in healthy adults with red eye.

From a clinical perspective, the application contains an adequate review of published clinical and non- clinical data with the active component. The therapeutic equivalence study also generated data on onset of symptomatic relief and sensory benefits of the new formulation.

Clinical safety The safety analysis data set included all subjects who used at least one dose of investigational product.

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Extent of Exposure Overall, 120 subjects were exposed to investigational products. All randomized subjects were administered the first dose of study eye drops at the study site. In addition, all randomized subjects administered the second and third doses of study eye drops at home in the afternoon and evening of Day 1. However, 11 subjects administered eye drops outside of the protocol specified time window (+30 minutes), one subject recorded three dose times for home dose two for the right eye, one subject did not record the dose times for the left eye, and one subject did not record the times for home doses for both eyes.

Adverse Events No adverse events were reported in this study.

Deaths, Other Serious Adverse Events, and Other Significant Adverse Events No deaths or other serious adverse events were reported. No subjects withdrew from the study due to an adverse event.

Clinical Laboratory Evaluation No clinical laboratory evaluations were performed in this study.

Vital Signs, Physical Findings, and Other Observations Related to SafetyNo follow-up vital signs, physical findings, or other observations related to safety were performed in this study.

Safety Conclusions All investigational products were well tolerated and no safety issues were identified. No adverse events were reported.

Legal Status Medicinal product not subject to medical prescription.

User Testing No full user test was provided but a bridging report, which is acceptable.

Summary Pharmacovigilance system The Applicant has submitted a signed Summary of the Applicant's and/or proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

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 Visine Yxin Hydro 0.5 mg/mL eye drops, solution.

Table SVIII.1: Summary of Safety Concerns Important identified risks None Important potential risks None Missing information None

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Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV BENEFIT RISK ASSESSMENT From a non-clinical and clinical perspective, the application contains an adequate review of published clinical,non-clinical data, and therapeutic equivalence was demonstrated. Approval is recommended. The application is approved. For intermediate amendments see current product information.

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