UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019

UKPAR

TABLE OF CONTENTS
Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 10

Steps taken after authorisation summary

Page 11

Summary of Product Characteristics

Page 12

Product Information Leaflet

Page 27

Labelling

Page 29

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019

LAY SUMMARY
The MHRA granted Aspire Pharma Limited Marketing Authorisations (licences) for
the medicinal product Amorolfine 5% w/v Medicated nail lacquer on 23 August 2012.
These products, to be available as prescription-only (PL 35533/0018) and pharmacy
(PL 35533/0019) medicines, are to be used to treat fungal infections of the nails and
fungal infections of the nails affecting the upper half or sides of the nail in up to two
nails.
These products contain the active ingredient amorolfine hydrochloride. Amorolfine
hydrochloride belongs to a group of medicines called antifungals. It can eradicate a
range of different fungi that can cause nail infections, a condition also known as
onychomycosis.
No new or unexpected safety concerns arose from these generic abridged applications
and it was, therefore, judged that the benefits of taking Amorolfine 5% w/v Medicated
nail lacquer outweigh the risks, hence Marketing Authorisations have been granted.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS
Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk benefit assessment

Page 10

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the MHRA considered
that the applications for Amorolfine 5% w/v Medicated nail lacquer (PL 35533/00189) could be approved.
The products are prescription-only (PL 35533/0018) and pharmacy (PL 35533/0019)
medicines for the treatment of:
onychomycoses caused by dermatophytes, yeasts and moulds (PL 35533/0018)
mild cases of distal and lateral subungual onchymycoses caused by dermatophytes,
yeasts and moulds, limited up to two nails (PL 35533/0019)
These applications were submitted according to Article 10.3 of 2001/83/EC, as
amended, claiming to be generic medicinal products of Loceryl 5% w/v Nail Lacquer
(PL 10590/0042), currently granted to Galderma (UK) Limited, but which was
originally licensed to Roche Products Limited in July 1991 (PL 00031/0285).
These products contain the active substance amorolfine hydrochloride. Amorolfine
hydrochloride is a topical broad-spectrum antimycotic, whos 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. Amorolfine from nail lacquer penetrates into and diffuses through
the nail plate and is thus able to eradicate poorly accessible fungi in the nail bed.

No new preclinical studies were conducted, which is acceptable given that the
applications were based on being hybrid medicinal products of an originator product
that has been licensed for over 10 years.
No bioequivalence data were submitted with these applications, in line with
CPMP/EWP/239/95 Notes for Guidance on the Clinical Requirements for Locally
Applied Locally Acting Products Containing Known Constituents. These applications
are based on the identicality of the physico-chemical properties to the reference
product. No therapeutic equivalence data is considered necessary because these are
cutaneous solutions, so a biowaiver can be applied.
As identical physicochemical properties to the reference product can be established, a
biowaiver is granted, in-line with CPMP/EWP/QWP/1401/98 Guideline on the
Investigation of Bioequivalence.
The RMS has been assured that acceptable standards of Good Manufacturing Practice
(GMP) are in place for these product types at all sites responsible for the manufacture,
assembly and batch release of these products.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

PHARMACEUTICAL ASSESSMENT
S.
Active substance
INN:
Amorolfine hydrochloride
Chemical name:
(+/-)-cis-2,6 (2R,6S) Dimethyl-4-[2-methyl-3(p-tert.pentylphenyl)propyl]morpholine hydrochloride
Structure:

Molecular formula:
Molecular weight:
Appearance:
Properties:

C21H36ClNO
353.97
White to almost white solid,
Soluble in water; freely soluble in methanol and ethanol;
slightly soluble in acetone and toluene; sparingly soluble in
2-propanol; and practically insoluble in n-Heptane

Synthesis of the drug substance from the designated starting materials has been
adequately described and appropriate in-process controls and intermediate
specifications are applied. Satisfactory specification tests are in place for all starting
materials and reagents and these are supported by relevant Certificates of Analysis.
An appropriate specification is provided for the active substance. Analytical methods
have been appropriately validated and are satisfactory for ensuring compliance with
the relevant specifications.
Appropriate proof-of-structure data have been supplied for the active pharmaceutical
ingredient. All potential known impurities have been identified and characterised.
Satisfactory Certificates of Analysis have been provided for all working standards.
Batch analysis data are provided and comply with the proposed specification.
Suitable specifications have been provided for all packaging used. The primary
packaging has been shown to comply with current guidelines concerning contact with
food.
Appropriate stability data have been generated supporting a suitable retest period
when stored in the proposed packaging.
P.
Medicinal Product
Other Ingredients
Other ingredients consist of the pharmaceutical excipients ammonio methacrylate,
copolymer A, triacetin, butyl acetate, ethyl acetate and ethanol.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

With the exception of butyl acetate, all of the excipients comply with their respective
European Pharmacopoeia monographs. Butyl acetate complies with a suitable
in-house specification.
None of the excipients are sourced from animal or human origin and no genetically
modified organisms (GMO) have been used in the preparation of these products.
Pharmaceutical Development
The objective of the development programme was to formulate a globally acceptable
and stable lacquer containing 5% amorolfine (as amorolfine hydrochloride) that could
be considered a generic medicinal product to Loceryl 5% w/v Nail Lacquer (PL
10590/0042).
A satisfactory account of the pharmaceutical development has been provided.
Comparative data of the physico-chemical properties have been provided for the
proposed and originator products.
Manufacturing Process
Satisfactory batch formulae have been provided for the manufacture of product, along
with an appropriate account of the manufacturing process. The manufacturing process
has been validated and has shown satisfactory results.
Finished Product Specification
The finished product specifications proposed are acceptable. Test methods have been
described and have been adequately validated. Batch data have been provided and
comply with the release specifications. Certificates of Analysis have been provided
for all working standards used.
Container-Closure System
The finished product is packaged in Type I (2.5ml) or Type 3 (5ml) glass bottles, with
polyethylene cap that is lined with polytetrafluoroethanol/polyethylene/polyethylene
terephthalate laminate.
Satisfactory specifications and Certificates of Analysis have been provided for all
packaging components. All primary packaging complies with the current European
regulations concerning materials in contact with food. All materials used in the cap
are in-line with Ph Eur 3.1.3, 3.1.5 and 3.2.2 and EC Directive 2002/72/EC.
The finished product is supplied in cardboard boxes in the following pack sizes:
PL 35533/0018 2.5ml (1x2.5ml), 5.0ml (1x5.0ml), 7.5ml (1x2.5ml &
1x5.0ml) and 10.0ml (2x5.0ml)
PL 35533/0019 3ml
All packs also contain cleansing swabs, polyethylene spatulas and nail files. The
polyethylene spatulas are in-line with Ph Eur 3.1.3 and 3.1.5. The swabs, spatulas and
nail files all have European Conformity or CE markings, in-line with EC
Directive 93/42/EEC (concerning Class 1 medical devices).

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

Stability of the product

Stability studies were performed in accordance with current guidelines on batches of
finished product packed in the packaging proposed for marketing. The data from these
studies support a shelf-life of 2 years, with the storage conditions Protect from heat.
Keep bottle tightly closed after use.
Bioequivalence/bioavailability
No bioequivalence study data have been submitted with these applications.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
The SPC, PIL and labels are pharmaceutically acceptable.
A package leaflet has been submitted to the MHRA along with results of consultations
with target patient groups ("user testing"), in accordance with Article 59 of Council
Directive 2001/83/EC, as amended. The results indicate that the package leaflet is
well-structured and organised, easy to understand and written in a comprehensive
manner. The test shows that the patients/users are able to act upon the information that
the package leaflet contains.
MAA forms
The MAA forms are pharmaceutically satisfactory.
Expert report
The pharmaceutical expert report has been written by an appropriately qualified
person and is a suitable summary of the pharmaceutical dossier.
Conclusion
The grant of marketing authorisations is recommended.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

NON-CLINICAL ASSESSMENT
As the pharmacodynamic, pharmacokinetic and toxicological properties of amorolfine
hydrochloride are well-known, no further non-clinical studies are required and none
have been provided.
The applicants non-clinical expert report has been written by an appropriately
qualified person and is satisfactory, providing an appropriate review of the products
pharmacology and toxicology.
A suitable justification has been provided for non-submission of an environmental
risk assessment. As this product is intended for generic substitution with a product
currently marketed, the environmental burden is not expected to increase. Thus, the
justification for non-submission of an Environmental Risk Assessment is accepted.
There are no objections to the approval of these products from a non-clinical
viewpoint.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

CLINICAL ASSESSMENT
Pharmacokinetics
No bioequivalence data were submitted with these applications, in line with
CPMP/EWP/239/95 Notes for Guidance on the Clinical Requirements for Locally
Applied Locally Acting Products Containing Known Constituents. These applications
are based on the identicality of the physico-chemical properties to the reference
product. No therapeutic equivalence data is considered necessary because it is a
cutaneous solution, so a biowaiver can be applied.
As identical physicochemical properties to the reference product can be established, a
biowaiver is granted, in-line with CPMP/EWP/QWP/1401/98 Guideline on the
Investigation of Bioequivalence.
Pharmacodynamics
No new pharmacodynamic data have been submitted with these applications and none
are required.
Efficacy
No new efficacy data have been submitted with these applications and none are
required.
Safety
No new safety data have been submitted with these applications and none are
required.
SmPC, PIL, Labels
The SmPCs, PILs and labels are medically acceptable. The SmPCs are consistent with
those for the originator product.
Clinical Expert Report
The clinical expert report has been written by an appropriately qualified physician and
is a suitable summary of the clinical aspects of the dossier.
Conclusion
The grant of marketing authorisations is recommended.

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

QUALITY
The important quality characteristics of Amorolfine 5% w/v Medicated nail lacquer
are well-defined and controlled. The specifications and batch analytical results
indicate consistency from batch to batch. There are no outstanding quality issues that
would have a negative impact on the benefit/risk balance.
NON-CLINICAL
No new non-clinical data were submitted and none are required for applications of
this type. A suitable justification has been provided for non-submission of an
Environmental Risk Assessment.
EFFICACY
No bioequivalence data were submitted with these applications and none are required.
Equivalence has been demonstrated through comparable physico-chemical properties
between these products and the originator product. No therapeutic equivalence studies
have been performed and none are required as the products are cutaneous solutions.
No new or unexpected safety concerns arise from these applications.
The SmPCs, PILs and labelling are satisfactory and consistent with those for the
originator product.
BENEFIT/RISK ASSESSMENT
The quality of the products is acceptable, and no new preclinical or clinical safety
concerns have been identified. Extensive clinical experience with amorolfine
hydrochloride is considered to have demonstrated the therapeutic value of the
compound. The benefit/risk is, therefore, considered to be positive.

10

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019

STEPS TAKEN FOR ASSESMENT

1

The MHRA received the Marketing Authorisation applications on 7 June 2010

Following standard checks and communication with the applicant the MHRA
considered the applications valid on 14 June 2010

Following assessment of the applications the MHRA requested further

information relating to the quality dossier on 8 October 2010, 20 June 2011, 22
December 2011 and 16 February 2012; no requests for further information were
made for the clinical dossier

The applicant responded to the MHRAs requests, providing further information

relating to the quality dossier on 30 March 2011, 20 September 2011, 25
January 2012 and 23 February 2012

The applications were determined on 23 August 2012

11

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019

STEPS TAKEN AFTER ASSESSMENT

Date
Application
submitted type

Scope

Outcome

12

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

AMOROLFINE 5% W/V MEDICATED NAIL LACQUER

PL 35533/0018
PL 35533/0019
SUMMARY OF PRODUCT CHARACTERISTICS
PATIENT INFORMATION LEAFLET
The current approved UK versions of the Summaries of Product Characteristics
(SmPCs) and Patient Information Leaflets (PILs) for these products are available on
the MHRA website.

13

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

LABELLING

14

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

15

UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

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UKPAR Amorolfine 5% w/v Medicated Nail Lacquer

PL 35533/0018-9

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