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
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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
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Cost-effective
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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
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➢
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
7
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
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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
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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
3
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