Beipackzettel - Amorolfin Oystershell 50 mg/ml wirkstoffhaltiger Nagellack
TABLE OF CONTENTS
ADMINISTRATIVE INFORMATION
| Name of the medicinal product in the RMS: | Amorolfin Oystershell 50 mg/ml wirkstoffhaltiger Nagellack |
| Name of the drug substance (INN name): | Amorolfine |
| Pharmaco-therapeutic group (ATC Code): | D01AE16 |
| Pharmaceutical form(s) and strength(s): | Medicated nail lacquer; 50 mg/ml |
| Reference Number(s) for the Decentralised Procedure: | DE/H/6029/001/DC (former UK/H/6017/001/DC) |
| Reference Member State: | DE (former UK) |
| Concerned Member States: | BE, LU |
| Applicant (name and address): | Oystershell nv Booiebos 24 9031 Drongen Belgium |
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I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy the Member States considered that the application for Amorolfin Oystershell 50 mg/ml wirkstoffhaltiger Nagellack (UK/H/6017/001/DC) is approvable.
The product is available in a pharmacy (P), and is indicated for the treatment of mild cases of distal and lateral subungual onychomycoses caused by dermatophytes, yeasts and moulds; treatment is limited to 2 nails.
The application was submitted using the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS) and Belgium, Germany and Luxembourg as Concerned Member States (CMSs). The application was submitted under Article 10(3) of Directive 2001/83/EC, as amended, as a hybrid application. The reference medicinal product for this application is Loceryl 5% w/v Medicated Nail Lacquer, originally granted to Roche Products Limited (PL 00031/0285) on 4 July 1991. The reference licence underwent a Change of Ownership (CoA) procedure and was authorised to the current Marketing Authorisation Holder, Galderma UK Limited (PL 10590/0042), on 19 April1999. The reference product has been authorised in the European community for more than 10 years, so the period of data exclusivity has expired.
Amorolfine 5% Medicated nail lacquer contains the active ingredient, amorolfine hydrochloride which is a topical antimycotic. It belongs to a new chemical class, and its fungicidal action is based on an alteration of the fungal cell membrane targeted primarily on sterol biosynthesis. The ergosterol content is reduced, and at the same time unusual sterically nonplanar sterols accumulate.
No new non-clinical or clinical studies were conducted for this application, which is acceptable given that this was a hybrid application for a similar product that has been licensed for over 10 years. A therapeutic equivalence study is not necessary to support this application for a topical solution. The RMS has been assured that acceptable standards of Good Manufacturing Practice are in place for this product type at all sites responsible for the manufacture, assembly and batch release 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. All Member States agreed to grant a Marketing Authorisation for the above product at the end of the procedure (Day 210 – 02 March 2016). After a subsequent national phase, the UK granted a Marketing Authorisation (PL 4415 7/0001) for this product on 17 March 2016.
After changing the RMS, Germany is the new RMS. The former procedure number was UK/H/6017/001/DC.
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II. QUALITY ASPECTS
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II.1 Introduction
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The product is presented as a clear, colourless to pale yellow solution. Each 1 ml of solution contains 55.74 mg of the active substance amorolfine hydrochloride (equivalent to 50 mg amorolfine). Other ingredients consist ofpha1maceutical excipients, Eudragit RL 100, triacetin, butyl acetate, ethyl acetate and ethanol. Appropriate justifications for the inclusion of each excipient have been provided. All excipients used comply with their respective European Pharmacopoeial monograph with the exception of butyl acetate which is controlled to an in-house specification. Satisfactory Certificates of Analysis for each excipient have been provided. The applicant has provided a declaration confirming that there are no materials of human or animal original contained in, or used in the manufacturing process for the proposed product. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients.
The finished product is licensed for marketing in an amber glass (Type I or Type Ill) bottle with a high density polyethylene (HDPE) cap, polytetrafluoroethylene (PTFE) liner and tamper evident ring. Each pack consists of one bottle and cleansing swabs, spatulas and nail files. The product is packaged in pack size of 2.5 ml. Specifications and Certificates of Analysis for all packaging components used have been provided. The glass bottles comply with Ph. Eur. requirements as well as the EU Directive 2002/72/EC.
II.2 Drug substance
INN:
Chemical name:
Structural formula:
Amorolfine hydrochloride
Cis-4-[ 4-(1 , 1-Dimethylpropyl) phenyl] –2– methylpropyl] –2,6-dimethyl-morpholine hydrochloride
C21H35NO ∙ HCl
Molecular formula:
Molecular mass: Appearance: Solubility:
353.98 g/mol
Amorolfine is a white or almost-white c1ystal or c1ystalline powder
Amorolfine is freely soluble in methanol and glacial acetic acid; soluble in
ethanol, sparingly soluble in acetonitrile, very slightly soluble in water.
Amorolfine hydrochloride is the subject of a European Pharmacopoeia (Ph. Eur.) monograph. All aspects of the manufacture and control of the active substance, amorolfine hydrochloride, are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.
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II.3 Medicinal product
Pharmaceutical Development
The aim of the pharmaceutical development programme was to produce robust, reproducible product that could be considered a generic medicinal product of Loceryl5% w/v Medicated Nail Lacquer (Galderma UK Limited). Suitable pharmaceutical development data have been provided for this application.
The physico-chemical properties of the drug product have been compared with the reference product. These data demonstrate that the proposed product can be considered a generic medicinal product of Loceryl 5% w/v Medicated Nail Lacquer (Galderma UK Limited). Comparative dissolution data were provided for the test and reference products. The dissolution profiles were found to be similar. A bioequivalence or therapeutic equivalence study has been waived on the bas is that the proposed product is a solution for topical use and the active is not systemically absorbed. Comparative in vitro dissolution and other physico-chemical parameters have been presented and are similar to the reference product Loceryl 5% w/v Medicated Nail Lacquer (Galderma UK Limited).
Manufacture of the product
A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Process validation data on commercial scale batches have been provided.
Finished Product Specification
The finished product specification proposed is acceptable. The test methods that have been described have been adequately validated. Batch data have been provided that comply with the release specification.
Stability of the Product
Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. The data from these studies support a shelf life of 3 years with storage conditions ‚Store below 30°C‘, ‚Protect from heat‘ and ‚Keep the bottle tightly closed and upright ‘.
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II.4 Discussion on chemical, pharmaceutical and biological aspects
The test product is pharmaceutically equivalent to the reference product, which has been licensed in the UK for over 10 years. Given the route of administration and pharmaceutical form, it is not necessary to perform a therapeutic equivalence study.
There are no objections to the approval of this application from a pharmaceutical point of view.
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III. NON-CLINICAL ASPECTS
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III.1 Introduction
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The pharmacodynamic, pharmacokinetic and toxicological prope1ties of amorolfine are well-known. As this is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on literature review is, thus, appropriate. The non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non·-clinical pharmacology, pharmacokinetics and toxicology.
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III.2 Pharmacology
Not applicable for this product type. Refer to section ‚III.1; Introduction‘ detailed above.
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III.3 Pharmacokinetics
Not applicable for this product type. Refer to section ‚III.1; Introduction‘ detailed above.
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III.4 Toxicology
Not applicable for this product type. Refer to section ‚III.1; Introduction‘ detailed above.
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III.5 Environmental Risk Assessment (ERA)
The active substance amorolfine hydrochloride has a log Kow > 4.5. The applicant is requested to submit Persistent Bioaccumulative and Toxic (PBT) substance assessment according to the EMA guideline. The requested outstanding information requires further studies to be completed before a final conclusion can be made on the ERA. Therefore, the applicant has committed to provide a revised ERA post -approval.
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III.6 Discussion on the non-clinical aspects
There are no objections to the approval of this appli1cation from a non-clinical point of view.
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IV. CLINICAL ASPECTS
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IV.1 Introduction
No new clinical data have been submitted and none are required for applications of this type. A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified physician.
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IV.2 Pharmacokinetics
No new data have been submitted and none are required for applications of this type. Amorolfin Oystershell 50 mg/ml wirkstoffhaltiger Nagellack is a hybrid application for a similar version of Loceryl 5% w/v Nail Lacquer. The use of the reference product is well-established in the UK. Both the reference product and the test product contain the same quantitative and qualitative composition of the active ingredient, amorolfine hydrochloride.
In accordance with the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401198 Rev. 1/Con**) the applicant is not required to submit a bioequivalence study if the product is to be administered as a topical solution containing the same active substance, in the same concentration as the currently authorised product. The applicant has not submitted a bioequivalence study, which is satisfactory.
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IV.3 Pharmacodynamics
No new pharmacodynamic data were submitted and none are required for applications of this type.
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IV.4 Clinical efficacy
No new data have been submitted and none are required for applications of this type.
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IV.5 Clinical safety
No new safety data have been submitted or required for this generic application. As amorolfine hydrochloride is a well-known substance with an acceptable adverse event profile, this is satisfactory.
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IV.6 Risk Management Plan
The Marketing Authorisation Holder (MAH) has submitted a risk management plan, in accordance with the requirements of Directive 200 1/83/EC as amended, describing the pha1macovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Amorolfin Oystershell 50 mg/ml wirkstoffhaltiger Nagellack.
A summary of safety concerns and planned risk minimisation activities, as approved in the RMP, is listed below:
| Safety concern | Routine risk minimisation measures | Additional risk minimisation measures |
| Allergic contact dermatitis | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer) 4.3. Contraindications 4.8. Undesirable effects | None proposed |
| Nail disorders (e.g. nail discoloration, broken nails, brittle nails) | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer)
| None proposed |
| Missing information: children and patients under 18 years old | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer) 4.2. Posology and method of administration | None proposed |
| Missing information: Elderly patients | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer) 4.2. Posology and method of administration | None proposed |
| Missing information: pregnancy | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer) 4.6 Pregnancy and lactation | None proposed |
| Missing information: Breastfeeding | Text in Summary of Product Characteristics (SPC) (Based on SmPC Amorolfine Oystershell 5% Nail Lacquer) 4.6 Pregnancy and lactation | None proposed |
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IV.7 Discussion on the clinical aspects
No new clinical data were submitted and none are required for this type of application. There are no objections to the approval of this application from a clinical viewpoint. The grant of a Marketing Authorisation is recommended for this application.
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V. USER CONSULTATION
The package leaflet has been evaluated via a user consultation study, in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the patient information leaflet (PIL) was English. The package leaflet meets the criteria for readability, as set out in the guideline on the readability of the label and package leaflet of medicinal products for human use.
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VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION