CRED NPM

CRED Prescription to to Non-Prescription Medicines Switch in Europe: Inside Out 6 Novem ber 202 4

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CRED Prescription to Non-Prescription Medicines Switch in Europe: Inside Out 6 November 2024 – online course

Programme

Speakers: Klavdija Kmetic and Christelle Anquez-Traxler, AESGP

Michelle Riddalls, PAGB Kate Stockman, Kenvue Berit Frei, Haleon Serenella Cascio and Orlane Jauvain, Opella

Time (UK)

Session

Speaker

9.15 Registration 9.30 Welcome from TOPRA 9:45 Introduction to the change of legal status from prescription to non-prescription – why selfcare and switch are important?

Christelle Anquez Traxler

Klavdija Kmetic , AESGP

10:00 Regulatory framework – part I

Christelle Anquez Traxler

-

Legal background

Klavdija Kmetic, AESGP

- Essential features about non-prescription medicines (and how they differ from Rx ie free pricing, advertising, distribution, etc) - NPM criteria - Switching process - What is harmonised (the law) and what is not (the market)

10:45 BREAK

11:00 Regulatory framework – Part II

Michelle Riddalls , PAGB

Switching in practice

- What other factors influence a switch - Strategic preparation before a switch - Data package - Risk minimisation and educational measures

12:00 Break out session

12:40 LUNCH BREAK

Programme subject to changes.

Programme Last amended: 25 October 2024

14:15 Case Study 1 - Switch strategies and challenges on the example of triptans in Germany

Berit Frei , Haleon

15:00 Case Study 2 – sildenafil switch

Kate Stockman ,

Kenvue

15:45 Short break

15:55 Case study 3 – Fexofenadine switch in key EU

Serenella Cascio

markets

Orlane Jauvain , Opella

16:40 Quiz

17:00 Close

Programme subject to changes.

Programme Last amended: 25 October 2024

Speaker Biographies

Christelle Anquez-Traxler Christelle Anquez-Traxler is Senior Regulatory Science and Strategy Lead at AESGP which is the European Association representing the selfcare industry. Her focus has always been on regulatory and science of non-prescription medicinal products with a particular passion for switch. She has been with AESGP 20 years and previously had been working in international affairs for the US FDA. She is a pharmacist by training with specialisation in regulatory affairs and health economics Klavdija Kmetic Klavdija Kmetic is the Regulatory Affairs and Policy Manager at the Association of the European Self-Care Industry (AESGP) in Brussels. In this role, she monitors regulatory, policy, and legislative developments affecting the self-care sector, with a particular focus on non prescription medicines and food supplements. Klavdija actively supports and contributes to the work of the AESGP Regulatory Affairs Committee and the work of dedicated expert groups. Additionally, she leads the AESGP expert group on switch and is passionate about improving the switch process and promoting switch to better support the self-care agenda in Europe. Michelle Riddalls Michelle Riddalls is Chief Executive of PAGB, the consumer healthcare association, which represents the manufacturers of branded over-the-counter (OTC) medicines, self-care medical devices and food supplements in the UK. Michelle is the leading spokesperson for the OTC sector on issues such as Brexit, self-care, reclassification and regulatory challenges. As part of this, Michelle has provided evidence to the House of Lords, and works closely with the Medicines and Healthcare products Regulatory Agency, Department of Health and Social Care, Office of Life Sciences and Number 10. Michelle is an expert in consumer healthcare regulation having worked in the sector for over two decades and has driven a number of successful product switches. She has received awards from TOPRA for her work in POM to OTC reclassifications and she was recognised by the Women in Trade Associations Power list in 2023 and 2024. Prior to joining PAGB, Michelle was Director of Regulatory Affairs for the Northern European Cluster at Pfizer Consumer Healthcare, where she was integral in the highly successful POM to GSL reclassification of Nexium Control and the Viagra Connect POM to P switch.

Berit Frei Berit Frei is Regulatory Affairs Director at the world-leading consumer health company Haleon (formerly GlaxoSmithKline Consumer Healthcare). With 15 years experiences in the development of OTC medicines she was involved in several switch applications and can provide in-depth knowledge on the European switch procedure and local specificities for the German market. Kate Stockman Kate Stockman is the Vice President Regulatory Affairs EMEA at Kenvue (formerly Johnson & Johnson Consumer Healthcare), the world’s largest pure play consumer healthcare company. She is responsible for the company’s EMEA regulatory organisation, providing strategic and operational leadership. Kate has 20+ years of pharma/consumer healthcare experience having previously worked at GSK, AstraZeneca, Pfizer & Haleon in a variety of regional and global regulatory leadership roles across a broad range of therapeutic areas. She has a strong track record of success in product development, from concept and early clinical development through to registration and life-cycle management of Rx & OTC medicines, medical devices, dietary supplements, cosmetics & herbal medicines. Kate has led and delivered Rx to OTC switches including Viagra Connect and Nexium OTC winning TOPRA Regulatory Excellence Awards in 2016 and 2108 for their innovative regulatory strategies and co authored RAPS Switch chapter on Rx to OTC Switch exUS . Kate has a Ph.D. in Molecular Microbiology from Guys Dental Hospital, Kings College London. Serenella Cascio Serenella is a regulatory professional with more than 25 years experience in the area of consumer healthcare, with a focus on consumer advertising, branding and Rx-to-OTC switch across different European Countries. Serenella has led and delivered Rx to OTC switches including Allevia, Allevia Hives, Nasacort, Cialis Together in the UK, Telfast in Spain , and Fexallegra, Mucosolvan, Buscopan Antiacido in Italy. Currently she is Science HUB Head for Western Europe in Opella, covering both Medical and Regulatory responsibilities. Orlane Jauvain A Doctor in Pharmacy with a Master’s degree in Regulatory Affairs, Orlane works for the French division of Opella Group as Regulatory Category Manager on Allergy and Cough & Cold. Orlane also have four years of experience in an international OTC regulatory department (AMEA, LATAM) on Marketing Authorization maintenance and project management.

05/11/2024

Introduction to the change of legal status from prescription to non-prescription medicines

Christelle Anquez-Traxler, Senior Regulatory Science and Strategy Lead, AESGP Klavdija Kmetic, Regulatory Affairs and Policy Manager, AESGP

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Why are non prescription medicines important?

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Can you imagine going to the doctor for a (simple) headache?

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Why self-care and switch are important

…to individuals

…to society

…for healthcare systems and national health funds?

…for selfcare companies, it’s innovation

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Individuals

• Ease and timeliness of access

Fast onset of treatment

Cost-effective

Empowerment

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Society

Public health

AMR

Health crisis

Selcare is a recognized concept by WHO: https://www.who.int/news room/fact-sheets/detail/self-care-health-interventions

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Self-Care pyramid

Self-care pyramid. From Self-Care: A Winning Solution for Citizens, Healthcare Professionals, Health Systems. AESGP; 2012.

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Healthcare system and national health funds

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Regulatory framework – part I

Christelle Anquez-Traxler, Senior Regulatory Science and Strategy Lead, AESGP Klavdija Kmetic, Regulatory Affairs and Policy Manager, AESGP

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Agenda

Change of legal status – legal background

Switch criteria

Switching process

Essential features about non-prescription

medicines

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Non-prescription medicines ID card

Name:

Non-Prescription medicines (NPM) defined by default in Article 72 of Dir.2001/83/EC

Synonym:

Over the counter medicine (OTC)

Antonym:

Prescription medicine (Rx) Four criteria defined in Article 71 of Dir.2001/83/EC

Family:

Self-care

Medicinal Product

Regulatory Category:

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Change of legal status

Directive 2001/83/EC

MA needed

None of the Rx criteria of article 71 • Direct or indirect danger

Art. 72 - definition by default

• Abuse-misuse • New substance • Injectable

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Change of legal status

switch

back switch

Legal status – national competence (except for CP)

Article 74 of Directive 2001/83/EC

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How to switch

Data requirements for switch

4 criteria explained

+1 year data exclusivity

Data exclusivity

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Switch criteria

Direct or Indirect danger

New substance

Abuse or misuse

Injectable

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Switch criteria

Serious known reactions can be acceptable if there is a clear identifiable risk group that can be excluded even in the absence of medical supervision

Direct danger

• Low general toxicity and no relevant reproductive toxicity, genotoxic or carcinogenic properties • Low risk of serious known adverse reactions in the general population • Very low risk of serious unknown reactions • No interactions with commonly used medicines which can produce serious reactions

Direct or Indirect danger

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Switch criteria

Indirect danger

• Risk of masking/hiding and risk of delaying adequate treatment

• Resistance

Reason why non-prescription medicines have usually short treatment of use!

Direct or Indirect danger

Direct or Indirect danger

Condition needs to be easily assessed by patient

Role of the leaflet critical

Risk to health small if unintentional misuse

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Switch criteria

Medicinal products frequently and to a very wide extent used incorrectly result in direct or indirect danger to human health UNDER PRESCRIPTION / BACK SWITCH

Abuse or misuse

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Switch criteria

New substance

Market experience in the general population / real conditions is a MUST

Activity and/or side-effects of substance contained in the medicinal product not yet well-known < New medicinal product on the market < Limited sales Modification to existing products (e.g. new strength, dose, route of administration, indication, new age group or combination of substances) must be evaluated

New substance

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Switch criteria

Injectable Additional risks and complexity of the route of administration

Injectable

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Other criteria for switch

National Healthcare System

Medical Culture

Risk Aversion

Patient Empowerment

Health Literacy

Political Will

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aciclovir (topical)

mometas one

omeprazol e

calcipotriol

sildenafil sumatriptan

DE

OTC

Rx

OTC

OTC

Rx

OTC

FR

OTC

Rx

Rx

OTC

Rx

Rx

IE

OTC

OTC

Rx

OTC

OTC

Rx

IT

OTC

Rx

Rx

OTC

Rx

Rx

PL

OTC

Rx

OTC

OTC

OTC

Rx

SE

OTC

Rx

OTC

OTC

Rx

OTC

SP

OTC

Rx

Rx

OTC

Rx

Rx

UK

OTC

OTC

OTC

OTC

OTC

OTC

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Any questions?

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Switch process itself differs across Europe

By API

By product

Options for market authorisation (in EU)

National

MRP / DCP

Centralised

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MA procedure

Centralised

MRP / DCP

National

Guarantees complete harmonisation all over the EU

The main path to market nowadays as allows to choose Member States

Procedure of choice in the past)

Not a success so far

Alli (orlistat) 2009 Pantoprazole 2009 Nexium (esomeprazole) 2013 ellaOne(ulipristal) 2015 Fortacin(prilocaine+ lidocaine) 2020 Desloratadine 2020

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Centralised procedure

DCP/MRP

Advantages

Disadvantages

Advantages

Disadvantages

Harmonisation

One dossier, one approval and one product information (PI)

Possibility to choose countries in the procedure

Mixed legal status procedure often the case and multiple procedures may be needed – can be 2 or 3 in parallel • Some countries may never gain OTC status. • Mixed legal status issues

Legal Status

• Included in the dossier and thus part of the evaluation • Opportunity to get OTC in all countries

Risk of OTC in none, even those that are favourable.

• Decided by NCA; CMS may change view on legal status during procedure • Can choose favourable MS for OTC

Future Rx to OTC Switch

As above, all countries Hard to get majority vote

Possible to select MS As above

Name

Harmonised

For non-unified market, difficult to capitalise on existing brands (eg pantroprazole which submitted 5 dossiers)

Flexibility

Discussions on naming may delay national phase

Maintenance

Easier

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Legal basis

Standalone application

8(3) - Full or full-mixed application

10(1) - Generic medicinal product application

10(3) - Hybrid medicinal product application

Variation Rx

NPM

10a -Well-established use application

10b - Fixed dose combination

10c - Informed consent

NPM

Rx

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Any questions?

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Product information

Labe l

Summary of Product Characterist ics (SmPC)

Leaflet

Instructions on use on pack – specific to NPM

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Advertising

Advertising to the general public allowed for non prescription medicines (general rule)

Exception = reimbursement

Enforcement / control different between countries

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Distribution – point of sales

Country-specific

Sub-classification

Pharmacy monopoly – AT, BE, CY, FI, FR, DE, HL, SK, SP

No pharmacy monopoly: IE, IT, PT, CZ, SE, UK

Online sales

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Pricing

Country specific

Free – determined by the economic rules of the market

In general non-reimbursable

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Key take aways

Definition and switch modalities harmonised at EU level

Legal status remains a national prerogative

Additional factors influencing switch

EU Market remains largely unharmonised

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Any questions?

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Regulatory Framework Part II

Michelle Riddalls CEO – PAGB, the consumer healthcare association

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Switching in practice

➢ What other factors influence a switch

➢ Strategic preparation before a switch

➢ Data package

➢ Risk minimisation and educational measures

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What other factors influence a switch?

Candidate Market

Resources

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What other factors influence a switch?

• Ensuring that the switch is going to be commercial viable

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Strategic preparation before a switch

Candidate benefits

Market assessment

OTC suitability Safety and risk

Supply

Efficacy

Profile

Resources

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OTC suitability

Can the product be legally switched?

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OTC suitability

Combination

Category

Self-diagnosis

How to use

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Safety & risk

Has all relevant safety data been reviewed?

Could the category of the active cause concern?

Is there evidence the candidate is likely to be used appropriately?

Has expert advice on the active/category been sought?

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Safety & risk

Use current Risk Management Plan (RMP) to identify risk and where RMP may need to be amended

Consider if post authorisation evaluation would contribute to safe use

Consider if risk management materials will be needed

Identify any possible concerns

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Candidate benefits

Widened access

Consumer need

Public health benefit

Improved clinical outcome

National healthcare saving

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Market assessment

Is the environment ‘ready’?

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Market assessment

Regulators

Government

HCPs

Consumers

Stakeholders

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Supply

Consideration should be given to the proposed supply model

• Will interactions with pharmacists be required?

• What is the consumer journey?

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Efficacy

During the reclassification process efficacy does not need to be specifically addressed unless there is a big change in indication, dosage regimen or patient population compared to the reference licence

➢ If that is the case, proof may be needed that the product is effective for those particular circumstances

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Profile

The company needs to develop the product profile - defining what they want the product to be and how it will appear on the market

Strength of the product

Indications

Dosage

Patient population

Warnings

Pack size

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Resources

It is important to understand:

The potential resources and costs involved

The level of expertise and engagement required

Any potential limitations in timelines/budget

What the company wants from the reclassification

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Resources

❖ Regulatory

❖ Dossier writers/submission

❖ Medical

❖ Epidemiological

❖ Clinical

❖ Project managers

❖ Marketing

❖ Sales/shopper team

❖ Packaging/artwork

❖ Trainers

❖ Consumer Insights

❖ Demand/supply managers

❖ Public Affairs

❖ Communications

❖ Pharmacovigilance

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Resources

PIL & label testing

Training

RMMs

Retailer/pharmacist interactions

Post authorisation evaluations

Advertising

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Data Package

• Switch Application to follow the ‘European Switch Guideline’

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Data Package

• Expert reports (non-clinical, clinical) - All switch criteria of the ‘European Switch Guideline’ to be reflected • Safety - Summary of animal and/or human studies - Experience of patient exposure (Post Marketing Surveillance data) - Information on adverse reactions - Summary of safety profile according to EU guidelines - Potential for drug interactions and consequences - Potential misuse / overdose - Consequences of incorrect assessment of symptoms - Consequences of incorrect or delayed diagnosis due to self medication

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Data Package Studies to support Rx-to-OTC Switch Applications

• Efficacy / safety study  Usually not required unless proposed OTC indication, dose, posology etc. not covered by existing data • Actual use study - Provides information on whether consumers can use the product correctly, safely and effectively in OTC setting  May be requested e.g., in case of first in class switch • Package leaflet - user consultation with target patient groups - Provides information on whether - package leaflet provides necessary information to consumer for appropriate use of the product - information in package leaflet is understood by the consumer  Mandatory

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Data Package - Data Exclusivity Eligibility for & Decision on Exclusivity (Dir. 2001/83/EC Art. 74a)

• Preclinical tests or clinical trials are significant, if they are - related to a new strength / posology - using a new route of administration, new pharmaceutical form - for a new indication, particularly when not previously approved for an OTC medicine or subpopulations • New safety/efficacy data (e.g., actual use studies) - to confirm safety/efficacy profile - likely to be eligible for exclusivity • Data exclusivity - One year stand alone period of protection - Applicant must apply for data exclusivity - Data exclusivity to be decided upon by each competent authority  in MRP & DCP ‘to use best endeavors’ to reach agreement

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Risk minimisation and educational measures

• Risk Management Plan (RMP)

Safety Specification

• Important Identified Risks • Important Potential Risks • Important Missing Information

Pharmacovigilance Plan / Activities

• Describes the PV activities and action plan for each safety concern • Routine: collecting adverse drug reactions • Additional: PASS studies, measuring effectiveness of RMMS

Risk Minimisation Plan / Measures

• The RMM Plan details the safety concerns for which RMM activities are proposed and discusses routine requirements and any additional provisions • Routine: SPC and Patient information leaflet • Additional: Provision of Safety Measures e.g. training or checklists

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Risk minimisation and educational measures

• Risk Minimisation Measures (RMMs)

➢ Strategies to minimise the impact of specific safety concerns

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Risk minimisation and educational measures

Checklists

➢ Should be based on the SmPC

➢ Include questions relevant to SmPC

➢ Include key ‘red flags’ in relation to the product

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Risk minimisation and educational measures

Training

➢ Pharmacy training / educational materials

➢ The SmPC should form the basis of the materials

➢ Materials should be proportionate to the training required and not be promotional or an unnecessary burden

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Risk minimisation and educational measures

Condition being treated

Pharmacy training / educational materials

Product being sold

➢ The SmPC should form the basis of the materials ➢ Materials should be proportionate to the training required and not be promotional or an unnecessary burden

Key safety risks

Examples of when the product can and can’t be sold

Case studies

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Risk minimisation and educational measures

Consumer education

➢ This is especially important to think about if it is a new OTC category

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In Conclusion

• What other factors influence a switch • Strategic preparation before a switch

Data package

• Risk minimisation and educational measures

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8

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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1.

NAME OF THE MEDICINAL PRODUCT

Silentio

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gram contains silentinine 20 mg and insonol 10 mg.

3.

PHARMACEUTICAL FORM

Cream. White, smooth, and homogenous cream.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Silentio cream is indicated for reducing the sensitivity to loud noises in adults and adolescents aged 12 years and older. It is particularly useful for individuals exposed to loud environments who experience discomfort due to noise.

Silencio is also indicated in the case of acute sonophobia and hyperacusia

4.2 Posology and method of administration

Posology

For topical use only.

1/ Indication 1 – to reduce sensitivity to noise:

• Adults and adolescents (12 years and older) : Apply approximately 1 gram of cream to each ear 20 minutes before anticipated noise exposure. Gently massage the cream into the skin around the outer ear.

• Maximum dose : Do not exceed 4 grams per day.

Silentio is not recommended for use in children under 12 years of age due to a lack of safety and efficacy data.

2/ Indication 2 – for acute sonophobia and hyperacusia

• Adults and adolescents (12 years and older) : Apply approximately 1 gram of cream to each ear 20 minutes before anticipated noise exposure. Gently massage the cream into the skin around the outer ear.

• Maximum dose : Do not exceed 4 grams per day.

Method of administration

Before applying the cream, ensure the skin is clean and dry. Apply only to the outer ear and avoid contact with the ear canal. Wash hands thoroughly after use.

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Precautions before handling:

Do not apply to broken or irritated skin.

• Avoid contact with mucous membranes, eyes, and nose.

4.3 Contraindications

Silentio is contraindicated in patients with:

• Known hypersensitivity to silentinine, insonol, or any excipients listed in section 6.1.

• Extremely large ears (e.g., macrotia) where topical application may lead to excessive systemic absorption.

• Musicians actively performing, due to potential interference with auditory perception.

Pregnancy (see section 4.6).

• Untreated bacterial, fungal, or viral infections of the skin, particularly around the ears.

• Open or ulcerated skin lesions near the application area.

4.4 Special warnings and precautions for use

Silentio is for cutaneous use only. Avoid contact with eyes, mucous membranes, or ingestion. In the event of accidental contact with eyes, rinse thoroughly with lukewarm water.

If signs of irritation or an allergic reaction occur, discontinue use immediately and consult a healthcare professional.

Use with caution in patients with compromised skin barriers (e.g., eczema or dermatitis).

Silentio should not replace noise protective equipment (e.g., earplugs or earmuffs) when such protective measures are recommended or required. The use of Silentio does not eliminate the need for proper hearing protection in environments with high noise exposure.

4.5 Interaction with other medicinal products and other forms of interaction

Caffeine: Concomitant use of caffeine may reduce the efficacy of Silentio in reducing auditory sensitivity.

Local anesthetics: The combined use of local anesthetics (e.g., lidocaine) may increase the absorption of the active ingredients in Silentio, leading to potential side effects.

4.6 Fertility, pregnancy and lactation

Pregnancy : Silentio is contraindicated in pregnancy due to a lack of sufficient safety data and potential risks to fetal auditory development. Breast-feeding : It is unknown whether the active ingredients of Silentio are excreted in human breast milk. Use caution when administering to nursing mothers. Avoid application on or near the breast.

Fertility : There are no data on the effects of Silentio on fertility.

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4.7 Effects on ability to drive and use machines

Silentio has minor influence on the ability to drive and use machines however given it will affect hearing it could lead to not hearing emergency vehicules and therefore is not advised in case of driving

4.8 Undesirable effects

Adverse reactions are listed by frequency and system organ class. The frequency of adverse reactions is defined as follows:

Very Common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very Rare (<1/10,000)

The most frequently reported adverse reactions include the following:

Common (≥1/100 to <1/10)

• Localized irritation, erythema, or pruritus at the application site

• Contact dermatitis in individuals sensitive to excipients

Uncommon (≥1/1,000 to <1/100)

• Temporary hearing changes, such as mild distortion or decreased clarity, typically resolving upon cessation of treatment

Rare (≥1/10,000 to <1/1,000)

Temporary full hearing loss

Excessive hair growth on the ears

Earlobe growth

Discoloration of ears

• Increased inclination to listen to Mariah Carey's "All I Want for Christmas"

Paediatric population : The safety profile in adolescents (12 years and older) is similar to that observed in adults.

Reporting of suspected adverse reactions : Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Silentio may be absorbed in sufficient amounts to produce systemic effects. Acute overdosage is very unlikely to occur, however, in the case of chronic overdosage or misuse the features of chronic hypoacusia may occur.

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : Auditory protective agents, ATC code: N07XX (not yet assigned).

Mechanism of action : Silentinine and insonol work synergistically to dampen auditory sensitivity by modulating nerve impulses related to sound processing in the auditory cortex.

Pharmacodynamic effects :

Silencio has a rapid onset of action and is effective within 5 minutes of application. The effectiveness of the medicinal product has been demonstrated to persist on repeat use over time

Clinical efficacy and safety : The efficacy of Silencia was demonstrated in two multi-centre, multinational, randomised, double blind, placebo controlled studies (SNORE1 and DODO2).

5.2 Pharmacokinetic properties

Absorption

The plasma levels of silentinine and insonol in male and female subjects were below the level associated with toxicity (5 000 ng/ml). olunteers had maximum plasma concentrations of silentinine which were less than 2% of toxic levels, and insonol which were less than 0.2% of toxic levels, after repeat dosing. Systemic exposure to silentinine and insonol and their metabolites (respectively 2,6 silentinidol and o-insonidlol), is low following application to the skin at the dose recommended.

Distribution

Silentinine: The steady-state volume of distribution is 1.1 to 2.1 L/kg after intravenous administration. It is reported to be 66% bound by plasma proteins, including alpha-1-acid glycoprotein. Silentinine can cross the blood brain barrier and the placenta and is distributed in breast milk. Insonol Following intravenous administration, the steady state volume of distribution of insonol is 0.6 to 4.1 L/kg. It is reported to be 42% bound to plasma proteins, including alpha-1-acid glycoprotein. Insonol crosses the blood-brain barrier and also crosses the placenta. Insonol is also distributed in breast milk.

Biotransformation

Silentinine is largely metabolised in the liver by cytochrome P450 (CYP 3A4) and probably to a minor extent in the skin. First pass metabolism is rapid and extensive and bioavailability is about 42% after oral doses. Silentinine is rapidly metabolised in the liver, by cytochrome P450. The metabolism of silentinine and insonol result in the formation of respectively 2,6-silentinidol and o-insonidlol, respectively, amongst other metabolites

Elimination

The terminal elimination half-life of silentinine from the plasma following intravenous administration is approximately 65 - 150 minutes and the systemic clearance is 10 - 20 mL/min/kg. Silentinine is excreted in the urine mainly as metabolites, with only a small proportion excreted unchanged. The elimination half-life of insonidol following intravenous administration is approximately 10 - 150 minutes. The systemic clearance is 18 - 64 mL/min/kg. insonidol is excreted in the urine mainly as its metabolites, with only a small proportion excreted unchanged

5.3 Preclinical safety data

5

Preclinical studies in animals showed no significant systemic toxicity with topical application. No evidence of mutagenic or carcinogenic potential was observed. In reproductive studies, high doses of Silentinine affected auditory development in animal models.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl Alcohol Carbomers Phospholipon 80H (Hydrogenated Soy Lecithin) Polysorbate 80 (Tween 80)

Propylene Glycol Vitamin E Acetate Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years. After first use, 18 weeks

6.4 Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

Aluminium container

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

AESGP

Avenue de Tervuren 7

B-1040 Brussels

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/14/522/007

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23/06/2010 Date of latest renewal: 23/05/2015

6

10. DATE OF REVISION OF THE TEXT

<{MM/YYYY}> <{DD month YYYY}>

7

05/11/2024

Case study 1: Switch Strategies and Challenges on the Example of Triptans in Germany

Berit Frei

Regulatory Affairs Director, Haleon Germany (former GSK Consumer Healthcare)

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals i Regulatory Affairs

1

Agenda

• Naratriptan switch Germany – A major milestone in the history of Rx to OTC switches • Switch strategy – Hurdles to overcome & product profile

• Switch criteria – risk assessment & minimization measures

• Switching process in Germany – as an example for substance-based switches

The Organisation for Professionals in Regulatory Affairs

2

1

05/11/2024

Why Naratriptan in OTC?

• Migraine is a chronic disease impacting 4.5% of adults in Germany

• Duration of untreated attack 4 – 72 hours

• Symptoms are severe and require immedate treatment (strong headache, but also accompanied by symptoms as nausea, dizziness and sentitivity to light or noise) • Compared to other analgesics or NSAIDs available as OTC, Triptans as Naratriptan provide a very selective acute treatment of migraine (binds to serotonin receptors leading to vasoconstriction of widened blood vessels in the brain)

Naratriptan

Widened blood vessel in the brain during migraine attack

Symptom relief by vasoconstriction of blood vessels

Early treatment beneficial

The Organisation for Professionals in Regulatory Affairs

Source: internal training material GSK Consumer Healthcare

3

Naratriptan switch- major milestone the history of Rx to OTC switches

• 1997 introduction of Naratriptan as 2 nd generation triptan with Rx status • Approval of switch in Germany 2006: first triptan with OTC status worldwide • Reclassification allows immediate treatment in case of an attack („ attack pack“) without the need to consult a doctor → public health benefit

The Organisation for Professionals in Regulatory Affairs

4

2

05/11/2024

Switch strategy

Self-diagnosis? Safe use without supervision of a doctor?

Hurdles to overcome:

• Mode of action of triptans: risk in cardiovascular diseases

• Risk of medicine induced headache (tension headache) with prolonged use

• Underlaying problems could not be detected in OTC use

• Self-diagnosis: Confusion with other forms of headache

The Organisation for Professionals in Regulatory Affairs

5

Switch strategy

Product profile for sucessful switch:

Strength: 2.5 mg

Pack size: 2 tablets

• Indication: For patients with diagnosed migraine

• Patient population: Limited to adults from 18 to 65 years

• Warnings & Contraindications: Hypertension,…

Development of specific OTC labelling

The Organisation for Professionals in Regulatory Affairs

6

3

05/11/2024

EU Switch Criteria

Direct or Indirect danger

New substance

Abuse or misuse

Injectable

The Organisation for Professionals in Regulatory Affairs

7

Switch criteria

Direct danger

• Well-established safety profile & low risk of serious adverse reactions based on post-marketing data • Minimal risk of incorrect use → use in non-migraine headaches, use in patients at risk of cardiovascular disease, prolonged use

Direct or Indirect danger

Labelling (Contraindications & Warnings) Pack size limitation Migraine questionnaire for pharmacists Risk Minimization

The Organisation for Professionals in Regulatory Affairs

8

4

05/11/2024

Risk minimization measure: Questionnaire for Pharmacies

Age?

• Has the migraine been diagnosed by a doctor? • Questions on contraindications and risk factors as cardiovascular diseases or other underlaying problems

minimise the impact of specific safety concerns

The Organisation for Professionals in Regulatory Affairs

9

Switch criteria

Indirect danger

• Headache non-specific symptom

rarely serious underlying pathology requiring medical attention

Risk Minimization

Restriction of indication to patients with diagnosed migraine • Migraine has very specific symptoms, which can be easily assessed and differentiated from other

Direct or Indirect danger

Direct or Indirect danger

forms of headache (disability, nausea, photophobia, self-limiting episodes)

• Treatment of triptanes very specific and will not relief other causes

The Organisation for Professionals in Regulatory Affairs

10

5

05/11/2024

Switch criteria

Abuse or misuse

• No abuse (no psychotropic effect)

• Very unlikely that Naratriptan will be misused in other indications due to specific mode of action

Abuse or misuse

Pack size restriction → prevents prolonged use (tension heachache) Risk Minimization

The Organisation for Professionals in Regulatory Affairs

11

Switch criteria

New substance

Several years market experience in general population available

No specific risk minimization required, but AEs were closely monitored after OTC status was obtained Risk Minimization

New substance

The Organisation for Professionals in Regulatory Affairs

12

6

05/11/2024

Switch criteria

Injectable

• Not applicable

Injectable

The Organisation for Professionals in Regulatory Affairs

13

National switch procedures in the EU

Substance-based Switch

Product-based Switch

vs.

Substance Product

Yes

The Organisation for Professionals in Regulatory Affairs

Source: Pharm Ind. 80, No. 3, Anquez-Traxler and Kroth, national switch procedures

14

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05/11/2024

Switch application – Data package

Application (independent from MAA)

Application form active substance and limitations e.g. to specific dosage form, indication,… → pre defined product profile

• Information if central application concerned

• Patients treated (per country, including Rx/OTC status)

• As MAH: Reference to licenses affected

• Switch rationale (Clinical overview, publications, safety data...)

• Proposed labelling for OTC use

The Organisation for Professionals in Regulatory Affairs

15

Substance based switch procedure

German switch procedure

Pharmaceutical Company

Federal Council

Variation submission for MAs to change to OTC status & labelling

Amendment of the Ordinance on Prescription-Only Medicinal Products

Expert Advisory Committee for

Prescription Only Issues

2x per year

YouTube Video on German switch process

The Organisation for Professionals in Regulatory Affairs

Source: Sträter Rechtsanwälte, Pharma Deutschland

16

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05/11/2024

Challenges in the German switch process

Process not optimal

• Application 2x a year, overall timeline sometimes difficult to predict • Limited involvement of applicant, decisions sometimes not transparent

Improvement 2020: Right to be heard for applicant, BfArM scientific opinion provided to applicant

No product-specific switch

• OTC status granted for all MAs, which fulfill conditions

• Can be a challenge in case of unharmonized labelling for DCPs

Limited market exclusivity

The Organisation for Professionals in Regulatory Affairs

17

Sucessful Triptan Switches in Germany

Year

Active ingredient

2006

Naratriptan

2009

Almotriptan

2020

Sumatriptan (tablets)

2024

Rizatriptan

The Organisation for Professionals in Regulatory Affairs

18

9

05/11/2024

Thank you!

Questions?

The Organisation for Professionals in Regulatory Affairs

19

10

06/11/2024

Case Study 1 – Sildenafil Switch

Dr Kate Stockman

Vice President Regulatory Affairs EMEA Kenvue

(Ex Global Rx to OTC Switch Lead @ Pfizer Consumer Health)

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals i Regulatory Affairs

1

Contents

Part A – Centralised Switch

• Background to the initial Viagra switch application

• ED definition and treatment

• Issues raised in 2008

• Part B – Decentralised Switch

• Key Hurdles to overcome

• Development of alternative switch model

• Key Learnings

The Organisation for Professionals in Regulatory Affairs

2

1

06/11/2024

Part a – Centralised Switch

The Organisation for Professionals in Regulatory Affairs

3

Lets go back to 2008……

The Organisation for Professionals in Regulatory Affairs

4

2

06/11/2024

The race was on for the first Centralised Rx to OTC Switch in Europe…

The Organisation for Professionals in Regulatory Affairs

5

But Viagra had to withdraw from the Race….

The Organisation for Professionals in Regulatory Affairs

Viagra, INN-sildenafil citrate

6

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