Public Assessment Report Decentralised Procedure

PAR Mometasone Furoate 0.1% w/w Cream
UK/H/2276/01/DC
Public Assessment Report
Decentralised Procedure
Mometasone Furoate 0.1% w/w Cream
UK/H/2276/001/DC
UK licence no: PL 33882/0032
Glenmark Pharmaceuticals SRO
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LAY SUMMARY
The Medicines Healthcare products Regulatory Agency granted Accord Healthcare Limited a
Marketing Authorisation (licence) for the medicinal product Mometasone Furoate 0.1% w/w
Cream. This medicine is available on prescription only.
Mometasone Furoate 0.1% w/w is used to help reduce redness and itchiness caused by
certain inflammatory skin problems such as psoriasis and some types of dermatitis.
The test product was considered the same as the original product Elocon 0.1% w/w Cream
(Schering Plough Limited, UK) based on the equivalence study submitted. No new safety
issues arose as a result of this study. No new or unexpected safety concerns arose from this
application and it was therefore judged that the benefits of using Mometasone Furoate 0.1%
w/w Cream outweigh the risks; hence a Marketing Authorisation has been granted.
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TABLE OF CONTENTS
Module 1: Information about initial procedure
Page 4
Module 2: Summary of Product Characteristics
Page 5
Module 3: Product Information Leaflet
Page 10
Module 4: Labelling
Page 16
Module 5: Scientific Discussion
Page 20
Module 6
1 Introduction
2 Quality aspects
3 Pre-clinical aspects
4 Clinical aspects
5 Overall conclusions
Page 20
Page 22
Page 24
Page 24
Page 29
Steps taken after initial procedure
Page 30
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Module 1
Product Name
Mometasone Furoate 0.1% w/w Cream
Type of Application
Generic, Article 10.3
Active Substance
Mometasone Furoate
Form
Cream
Strength
1mg/g
MA Holder
Glenmark Pharmaceuticals S.R.O
RMS
UK
CMS
Procedure Number
Bulgaria, Czech Republic, Hungary, Lithuania, Poland, Portugal,
Romania and Slovakia.
UK/H/2276/001/DC
Timetable
Day 210 – 09/03/2011
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Module 2
Summary of Product Characteristics
1
NAME OF THE MEDICINAL PRODUCT
Mometasone Furoate 0.1% w/w Cream
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
One gram of cream contains 1 mg of mometasone furoate (0.1 % w/w mometasone furoate).
Excipients:
80 mg propylene glycol monopalmitostearate per gram cream
70 mg stearyl alcohol per gram cream
Traces, up to a maximum of 0.015mg Butylated hydroxytoluene (E321) per gram cream
For a full list of excipients, see section 6.1
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PHARMACEUTICAL FORM
Cream
White to off-white, smooth cream.
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4.1
CLINICAL PARTICULARS
Therapeutic indications
Mometasone Furoate 0.1% w/w Cream is indicated for the symptomatic treatment of inflammatory
skin conditions which respond to external treatment with glucocorticoids such as atopic dermatitis and
psoriasis (excluding widespread plaque psoriasis).
4.2
Posology and method of administration
Adults (including elderly patients), adolescents and children aged 6 years and over:
A thin film of Mometasone Furoate 0.1% w/w Cream should be applied to the affected skin area once
daily. One fingertip unit (a line from the tip of an adult index finger to the first crease) is enough to
cover an area twice the size of an adult hand.
Use of a weaker corticosteroid is often advisable when there is a clinical improvement.
Mometasone Furoate 0.1% w/w Cream should not be used for long periods (over 3 weeks) or on large
areas (over 20% of body surface area). In children a maximum of 10% of body surface area should be
treated.
Use of topical corticosteroids in children aged 6 years and over, or on the face should be limited to the
least amount compatible with an effective therapeutic regimen, and duration of treatment should be no
more than 5 days.
Children below 6 years
Mometasone Furoate 0.1% w/w Cream is not recommended for use in children below 6 years of age
due to insufficient data on safety (see section 4.8).
4.3
Contraindications
Hypersensitivity to the active substance mometasone furoate or to any of the excipients.
Mometasone Furoate 0.1% w/w Cream is contraindicated in facial rosacea, acne vulgaris, perioral
dermatitis, perianal and genital pruritis, napkin eruptions, bacterial (e.g. impetigo), viral (e.g. herpes
simplex, herpes zoster and chickenpox) and fungal (e.g. candida or dermatophyte) infections, varicella,
tuberculosis, syphilis or post-vaccine reactions.
4.4
Special warnings and precautions for use
Mometasone Furoate 0.1% w/w Cream should not be used on the eyelids.
Caution should be observed in patients who are hypersensitive to any other corticosteroid.
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If irritation or sensitisation develop with the use of Mometasone Furoate 0.1% w/w Cream, treatment
should be withdrawn and appropriate therapy instituted.
Should an infection develop, use of an appropriate antifungal or antibacterial agent should be
instituted. If a favourable response does not occur promptly, the corticosteroid should be discontinued
until the infection is adequately controlled.
Local and systemic toxicity is common especially following long continued use on large areas of
damaged or broken skin, in flexures and with polythene occlusion. Caution should be exercised when
large areas of the body are treated and long term continuous therapy should be avoided in all patients
irrespective of age.
Mometasone Furoate 0.1% w/w Cream should not be applied to broken skin.
Topical steroids may be hazardous in psoriasis for a number of reasons including rebound relapses
following development of tolerance, risk of centralised pustular psoriasis and development of local or
systemic toxicity due to impaired barrier function of the skin. If used in psoriasis careful patient
supervision is important.
As with all potent topical glucocorticoids, avoid sudden discontinuation of treatment. When long term
topical treatment with potent glucocorticoids is stopped, a rebound phenomenon can develop which
takes the form of a dermatitis with intense redness, stinging and burning. This can be prevented by
slow reduction of the treatment, for instance continue treatment on an intermittent basis before
discontinuing treatment.
Hyperglycaemia and glucosuria can occur in some patients after topical application due to systemic
absorption.
Glucocorticoids can change the appearance of some lesions and make it difficult to establish an
adequate diagnosis and can also delay the healing.
Mometasone Furoate 0.1% w/w Cream contains propylene glycol, which may cause skin irritation.
Mometasone Furoate 0.1% w/w Cream contains stearyl alcohol and also butylated hydroxytoluene,
which may cause skin irritations/reactions (e.g. contact dermatitis), or irritation to the eyes and mucous
membranes.
4.5
Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed
4.6
Pregnancy and lactation
Pregnancy
Corticosteroids cross the placenta. There is very limited data on the use of topical mometasone during
pregnancy. After systemic use of high dose corticosteroids, effects on the fetus/neonate have been
described (intra-uterine growth retardation, adrenocortical suppression, cleft palate).
Animal studies have shown reproduction toxicity and teratogenity (see section 5.3). The potential risk
for humans is unknown.
Although systemic exposure is limited, Mometasone Furoate 0.1% w/w Cream should only be used
during pregnancy when clearly necessary.
Pregnant women should not use the product on large skin areas for long periods.
Lactation
It is not known whether mometasone is excreted into breast milk. However, topical application of
mometasone on limited skin areas is not likely to result in any risk for breastfed children. The product
should not be applied on the breasts directly before breastfeeding.
4.7
Effects on ability to drive and use machines
Mometasone Furoate 0.1% w/w Cream has no influence on the ability to drive and use machines.
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4.8
UK/H/2276/01/DC
Undesirable effects
Adverse reactions are listed in Table 1 according to MedDRA system organ class and in decreasing
frequency 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)
Not known (frequency cannot be estimated from the available data)
Adverse reactions that have been reported in connection with external corticosteroid treatment include:
Table 1: Treatment-related adverse reactions reported by body system and frequency
Skin and subcutaneous tissue disorders
Common:
Mild to moderate burning sensations at the application
site, tingling/stinging, pruritis, bacterial infections,
paraesthesia,furunculosis and local skin atrophy.
Uncommon:
Striae, irritation, hypertrichosis, hypopigmentation,
perioral dermatitis, maceration of the skin, allergic
contact dermatitis, papulous roseacea like dermatitis
(facial skin), acneiform reactions, capillary brittleness
(ecchymoses), miliaria, dryness, sensitisation
(mometasone), folliculitis.
Infections and parasitic infestations
Uncommon
Secondary infection.
Vascular disorders
Very rare
Telangiectasis
An increased risk of systemic effects and local adverse events exists with frequent dosing, treatment of
large areas or in the long term and also the treatment of intertriginous areas or with occlusive dressings.
Hypopigmentation or hyperpigmentation has been reported in isolated cases (rare) in connection with
other steroids and may therefore occur with Mometasone Furoate 0.1% w/w Cream.
Side effects which have been reported with systemic glucocorticoids – including adrenal suppression –
may also occur with topically applied glucocorticoids.
Paediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced
hypothalamic-pituitary-adrenal axis suppression and Cushing’s syndrome than mature patients because
of a larger skin surface to body weight ratio. Chronic corticosteroids therapy may interfere with the
growth and development of children.
Intracranial hypertension has been reported in paediatric patients receiving topical corticosteroids.
Manifestations of intracranial hypertension include bulging fontanelles, headaches and bilateral
papilloedema.
4.9
Overdose
Excessive long-term use of external corticosteroids may suppress HPA axis function and give rise to
secondary adrenocortical insufficiency. If suppression of the HPA axis has been reported, it should be
endeavoured, with the usual caution being exercised in these situations, to reduce the frequency of
applications or to try to withdraw the drug.
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5.1
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PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Corticoids, potent (group III)
ATC code: D07AC13
Mometasone Furoate 0.1% w/w Cream is a potent glucocorticoid, group III.
The active substance, mometasone furoate, is a synthetic, non-fluorinated glucocorticoid with a furoate
ester in position 17.
Like other corticosteroids for external use, mometasone furoate exhibits marked anti-inflammatory
activity and marked anti-psoriatic activity in standard animal predictive models.
In the croton oil assay in mice, mometasone (ED50 = 0.2 μg/ear) was equipotent to betamethasone
valerate after single application and about 8 times as potent after five applications (ED50 =
0.002 μg/ear/day versus 0.014 μg/ear/day).
In guinea pigs, mometasone was approximately twice as potent as betamethasone valerate in reducing
m.ovalis-induced epidermal acanthosis (i.e. anti-psoriatic activity) after 14 applications.
5.2
Pharmacokinetic properties
Results from percutaneous absorption studies have indicated that systemic absorption following topical
application of mometasone furoate cream 0.1 % is minimal. The results show that about 0.7 % of the
active ingredient is absorbed by the intact skin in 8 hours (without using an occlusive dressing).
Characterisation of metabolites was not feasible owing to the small amounts present in plasma and
excreta.
5.3
Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already
included in other sections of the SPC.
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6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Hexylene Glycol
Water, purified
Beeswax white
Propylene Glycol Monopalmitostearate
Promulgen G (Stearyl alcohol and Ceteareth – 20)
Titanium Dioxide (E171)
Aluminium Starch octenylsuccinate
Phosphoric acid concentrated (for pH adjustment)
Paraffin, white soft
Butylated hydroxytoluene (E321) – as an antioxidant in paraffin, white soft.
6.2
Incompatibilities
Not applicable
6.3
Shelf life
2 years
After first opening: 12 weeks
6.4
6.5
Special precautions for storage
Store below 250C
Do not freeze
Nature and contents of container
15g, 20g, 30g latex lacquered aluminium tubes with high density polyethylene screw
cap in a cardboard carton. Each carton contains one tube.
Not all packs sizes may be marketed.
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6.6
Special precautions for disposal
No special requirements
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MARKETING AUTHORISATION HOLDER
Glenmark Pharmaceuticals s.r.o., City Tower, Hvezdova 1716/2b, 140 78 Prague 4, Czech Republic.
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MARKETING AUTHORISATION NUMBER(S)
PL 33882/0032
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DATE OF FIRST AUTHORISATION/RENEWAL OF THE
05/04/2011
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DATE OF REVISION OF THE TEXT
05/04/2011
AUTHORISATION
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Module 3
PATIENT INFORMATION LEAFLET
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Module 4
Labelling
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Module 5
Scientific discussion during initial procedure
I
INTRODUCTION
On 9th March 2011, Bulgaria, Czech Republic, Hungary, Lithuania, Poland, Portugal,
Romania, Slovakia and the UK agreed to grant a Marketing Authorisation (MA) to Glenmark
Pharmaceuticals S.R.O for the medicinal product Mometasone Furoate 0.1% w/w Cream.
The MA was granted via a Decentralised Procedure (DCP), with the UK as Reference
Member State (RMS UK/H/2272/001/DC). After the national phase, an MA was granted in
the UK on 5th April 2011 (PL 33882/0032).
This is an abridged application for Mometasone Furoate 0.1% w/w Cream submitted under
Article 10.3 of 2001/83 EC, as amended. The application refers to the reference medicinal
product Elocon 0.1%w/w Cream (PL 00201/0117), authorised to Schering Plough Limited on
19th November 1991. The reference product has been registered in the EEA for more than 10
years, hence the period of data exclusivity has expired. With the UK as the Reference
Member State Mometasone Furoate 0.1% w/w Cream, has been shown to be a generic
medicinal product of Elocon 0.1%w/w Cream which was first granted a licence in the UK to
Schering Plough Limited, on 19th November 1991.
Based on the review of the data on quality, safety and efficacy, the RMS considers that the
application for Mometasone Furoate 0.1% w/w Cream, for the symptomatic treatment of
moderate to severe inflammatory skin conditions which are not caused by micro organisms,
such as psoriasis (excluding widespread plaque psoriasis) and atopic dermatitis, which
respond to external treatment with glucocorticoids, is approvable.
The proposed product is indicated for cutaneous use, for the symptomatic treatment of
moderate to severe inflammatory skin conditions which are not caused by micro organisms,
such as psoriasis (excluding widespread plaque psoriasis) and atopic dermatitis, which
respond to external treatment with glucocorticoids. Each gram of cream contains 1 mg of
mometasone furoate. A thin film of the product is applied to the affected area once daily.
The product is not to be used for a period longer than 3 weeks or on over 20% of body
surface area (10% of body surface area in children > 6 and treatment no more than 5 days).
The active substance, mometasone furoate, is a synthetic, non-fluorinated glucocorticoid with
a furoate ester in position 17.
Like other corticosteroids for external use, mometasone furoate exhibits marked antiinflammatory activity and marked anti-psoriatic activity in standard animal predictive
models.
No new preclinical studies were conducted and none are required for an application of this
type. To support the application the application has submitted a pilot and pivotal study to
establish equivalence of the vasoconstriction response between the proposed product and the
reference product. These studies are described in the Clinical Aspects section.
The RMS has been assured that acceptable standards of GMP are in place for these product
types at all sites responsible for the manufacture, batch release and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current
manufacturer authorisations issued by inspection services of the competent authorities as
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certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current
GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange
of information’ issued by the inspection services of the competent authorities (or those
countries with which the EEA has a Mutual Recognition Agreement for their own territories)
as certification that acceptable standards of GMP are in place at those non-Community sites.
The RMS has been reassured that the submitted studies have been carried out in accordance
with GCP, and agreed ethical principles.
The RMS considers that the pharmacovigilance system as described by the MAH fulfils the
requirements and provides adequate evidence that the MAH has the services of a qualified
person responsible for pharmacovigilance and has the necessary means for the notification of
any adverse reaction suspected of occurring either in the Community or in a third country.
The Marketing Authorisation holder (MAH) has provided adequate justification for not
submitting a Risk Management Plan (RMP). As the application is for a generic version of an
already authorised reference product, for which safety concerns requiring additional
minimisation have not been identified, routine pharmacovigilance activities are proposed and
a risk minimisation system is not considered necessary. The reference product has been in
use for many years and the safety profile of the active is well-established.
The MAH has provided adequate justification for not submitting an Environmental Risk
Assessment (ERA). This was an application for a generic product and there is no reason to
conclude that marketing of this product will change the overall use pattern of the existing
market. The excipients used in the product formulation are commonly used pharmaceutical
compounds. There are no environmental concerns associated with the method of manufacture
or formulation of the product.
II.
ABOUT THE PRODUCT
Name of the product in the Reference Member State
Mometasone Furoate 01% w/w Cream
Name(s) of the active substance(s) (INN)
Pharmacotherapeutic classification
(ATC code)
Mometasone Furoate
Pharmaceutical form and strength(s)
Reference numbers for the Mutual Recognition
Procedure
Reference Member State
Member States concerned
Marketing Authorisation Number(s)
Name and address of the
authorisation holder
Corticosteroids, potent (group III)
D07AC13
Cream, 1mg/g
UK/H/2276/01/DC
United Kingdom
Bulgaria,
Czech
Republic,
Hungary,
Lithuania, Poland, Portugal, Romania and
Slovakia.
PL 33882/0032
Glenmark Pharmaceuticals S.R.O
City Tower, Hvezdova 1716/2b, 140 78
Prague 4, Czech Republic.
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III
III.1
S.
UK/H/2276/01/DC
SCIENTIFIC OVERVIEW AND DISCUSSION
QUALITY ASPECTS
ACTIVE SUBSTANCE
General Information
Nomenclature
INN: Mometasone Furoate
Structure
Description:
White or almost white powder.
Solubility:
Practically insoluble in water; soluble
dichloromethane; slightly soluble in alcohol.
Chemical name:
Pregna-1,4-diene-3,20-dione-9,20-dichloro-17-[(2furanylcarbonyl)oxy]-11-hydroxy-16-methyl-(11β,16α)
9,21-dichloro-11β, 17-dihydroxy-16 α -methylpregna-1,4-diene-3,20dione-17-furane-2-carboxylate
Molecular formula:
C27H30Cl2O6
Molecular Weight
521.43
in
acetone
and
in
Manufacture
All aspects of the manufacture and control of the active substance mometasone furoate are
covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of
Suitability.
DRUG PRODUCT
Description & Composition
The drug product is presented as a white to off-white smooth cream. Each 1g of cream
contains 1mg (0.1% w/w) of the active ingredient mometasone furoate.
Other ingredients consist of pharmaceutical excipients, hexylene glycol, purified water,
beewax white, propylene glycol monopalmitostearate, promulgen G (Stearyl alcohol and
Ceteareth-20), titanium dioxide (E171), aluminium starch octenylsuccinate, phosphoric acid
concentrated (for pH adjustment), paraffin, white soft, butylated hydroxytoluene (E321)- as
an antioxidant in paraffin, white soft.
All excipients used comply with their respective European Pharmacopoeial monograph with
the exception of promulgen G and aluminium starch octenylsuccinate which are controlled to
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in-house specifications and hexylene glycol which is controlled according to National
Formulary (NF) specification. All excipients have been previously been approved for
cutaneous use. Satisfactory certificates of analysis have been provided for all excipients.
The MAH has provided a declaration confirming that there are no materials of human or animal
origin contained in or used in the manufacturing process for the product.
There are no novel excipients used.
Impurity profiles
Comparative impurity profiles were provided for test and reference products. The impurity profiles
were found to be similar, with all impurities within the specification limits.
Pharmaceutical development
The aim of the pharmaceutical development programme was to develop a drug product that could
be considered therapeutically equivalent to the reference product Elocon 0.1% w/w Cream
(Schering Plough Limited). Details of the pharmaceutical development of the drug product have
been supplied and are satisfactory.
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 Elocon 0.1% w/w Cream (PL 00201/0117) licensed to Schering Plough
Limited.
Manufacture
A description and flow-chart of the manufacturing method has been provided.
In-process controls are appropriate considering the nature of the product and the method of
manufacture. Process validation studies have been conducted and are accepted. Satisfactory
analytical results from batches results from batches representative of commercial scale were
provided.
Finished Product Specification
Finished product specifications are provided for both release and shelf-life, and are
satisfactory; they provide an assurance of the quality and consistency of the finished product.
Acceptance limits have been justified with respect to conventional pharmaceutical
requirements and, where appropriate, safety. Test methods have been described and
adequately validated, as appropriate. Batch data are provided for four pilot scale batches of
the product, which demonstrate that the batches are compliant with the proposed release
specifications. The MAH has provided a commitment to validate the first three commercial
scale batches. Certificates of Analysis have been provided for any reference standards used.
Container Closure System
The finished product is presented in latex lacquered aluminium tubes with high density polyethylene
screen caps in pack sizes of 15g, 20g or 30g. The tubes are packaged individually with the Product
Information Leaflet (PIL) into the cardboard outer cartons. The MA Holder (MAH) has stated that
not all pack sizes may be marketed however, the MAH has committed to submitting the proposed
packaging/labelling for any pack size before it is marketed. The tubes satisfy the requirements of
Directive 2002/72/EC (as amended). Specifications and Certificates of Analysis for all packaging
components used have been provided, and are satisfactory.
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Stability
Finished product stability studies have been conducted in accordance with current guidelines
and results were within the proposed specification limits. Based on the results, a shelf-life of
2 years has been set, which is satisfactory. The shelf-life after first opening a tube is 12
weeks. Storage instructions are, “Store below 25 °C” and “Do not freeze”.
Therapeutic Equivalence Study
Bioequivalence studies are not necessary to support this application. For products for local
application intended to act without systemic absorption, the approach to determine equivalence
based on systemic measurements is not applicable and pharmacodynamic or comparative clinical
studies are required. The applicant has submitted a pilot and pivotal studies to establish therapeutic
equivalence of the vasoconstriction response between the proposed product and the reference
product, Elocon 0.1% Cream. The study is evaluated in the Clinical Aspects section.
Expert Report
A satisfactory quality overview is provided, and has been prepared by an appropriately qualified
expert. The CV of the expert has been supplied. In accordance with the medicines legislation, the
product shall not be marketed
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
The SmPC, PIL and labelling are pharmaceutically acceptable. Text versions of the PIL and labels
have been provided and are satisfactory. In accordance with the medicines legislation, the product
shall not be marketed in the UK until prior approval of the product labelling and leaflet mock-ups
has been obtained.
The applicant has submitted results of PIL user testing. The results indicate that the PIL 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 is contains.
Conclusion
It is recommended that a Marketing Authorisation is granted for this application.
III.2 Non clinical aspects
The pharmacological, pharmacokinetic and toxicological properties of mometasone furoate
are well- known. As mometasone furoate is a widely used, well-known active substance, no
further studies are required and the applicant has provided none. An overview based on a
literature review is thus appropriate. An adequate overview has been written by as suitably
qualified person.
There are no objections to the approval of mometasone furoate from a non-clinical point of
view.
III.3 Clinical aspects
Pharmacokinetics
The active substance, mometasone furoate, is a synthetic, non-fluorinated glucocorticoid.
Like other corticosteroids for external use, mometasone furoate exhibits marked antiinflammatory activity and marked anti-psoriatic activity in standard animal predictive
models.
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To support the application, the applicant has submitted a pilot and pivotal study to establish
equivalence of the vasoconstriction response between the proposed product and the reference
product, Elocon cream. The active substance, mometasone furoate, is a synthetic, nonfluorinated glucocorticoid. Like other corticosteroids for external use, mometasone furoate
exhibits marked anti-inflammatory activity and marked anti-psoriatic activity in standard
animal predictive models.
Pilot study
This was a single exposure, dosing range study to evaluate the vasoconstriction activity of
topically delivered mometasone furoate cream 0.1% in normal skin in healthy adult subjects.
Methodology
Subjects had ten 4-cm² sites on both forearms evaluated for vasoconstriction response to a
single lot of ELOCON Cream following different durations of dose application ranging from
5 minutes to 480 minutes, in duplicate. Two sites on each forearm remained untreated to
serve as control sites. All sites remained un-occluded after application. Vasoconstriction
response (skin blanching) was evaluated by chromameter measurement at pre-dose, and after
dose removal at 11 time points up to 24 hours.
The study followed the dose-duration response study design presented in the FDA guidance.
The objective of the study was to identify ED50, the dose which produced half the maximal
effect in terms of vasoconstriction, in the reference product. This dose would then identify
the three doses to be included in the pivotal study.
Statistical analysis
Vasoconstriction data analyses were conducted as described in the FDA Guidance.
Chromameter L*a*b*-a values for each time point and site were corrected for baseline
reading and by the untreated site reading. Negative Area Under the Effect Curve (AUEC)
values for the duration of 24 hours post dose removal were calculated from the final
corrected (a*) values using the trapezoidal rule. Maximum effect (Emax) and ED50 were
determined using software specifically designed for population modelling.
Results
Data from all subjects were included in the statistical analysis. The results are presented in
the table below.
Conclusions on the pilot study:
The recommended methodology has been used to identify appropriate doses for the pivotal
study.
Based on the ED50 of 56.20, an appropriate dose for evaluating equivalence in a pivotal
therapeutic equivalence study is 60 minutes with D1=30 minutes and D2=120 minutes.
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UK/H/2276/01/DC
Pivotal study
This was a single-blind, single-exposure study in healthy subjects to compare the dose
duration vasoconstriction response of Elocon cream (reference product) and a test
formulation of mometasone 0.1% cream using the vasoconstriction assay. The study was
designed according to current guidelines.
Each subject had 10 sites on both forearms evaluated for vasoconstriction response to active
treatment, test and reference formulations, and two untreated sites which acted as controls.
Dose durations were based on D1 (30 min), D2 (120 min) and ED50 (60 min) values for the
reference (Elocon) as determined in pilot study. The test formulation was dosed for 60 min,
using the same ED50.
Vasoconstriction response was evaluated by chromameter
measurement at pre-dose and for 24 hours after dose removal at 11 time points (1 to 24
hours).
Assessment of skin blanching
Pharmacodynamic response to the topical corticosteroids at various time periods following
each dose and removal were assessed by visual score (screening only) and by chromameter
measurement (study assessment period).
Visual Score
Visual score assessment (for screening) was based on the following criteria:
0
no pallor; no change from surrounding area
1
mild pallor; slight or indistinct within application site
2
moderate pallor; discernible but diffuse within application site
3
moderate pallor; clean, distinct within application site
4
intense pallor; clean, distinct within application site
Chromameter Measurement
Quantification of skin blanching was obtained by chromameter (Minolta Inc., Model CR300)
during study conduct. The chromameter was programmed for recording the L*a*b* colour
scale and set to automatically collect three back-to-back readings to obtain the internally
calculated mean.
Statistical Methods
Vasoconstriction data analysis was conducted according to the FDA guidance. Chromameter
scores were tabulated and collated to site. The final assessment for each site was first
adjusted for that site’s baseline reading and then corrected for the mean of the untreated
control sites. Negative Area Under the Effect Curve (AUEC) values for the 24 hours after
dose removal were calculated from the final corrected values using the trapezoidal rule.
Only the data of ‘detectors’, individual subjects whose negative AUEC values at D1 and D2
were both positive and met the dose duration response criterion below, were included in the
final analysis. The criterion is:
AUEC at D2 > 1.25
AUEC at D1
A 94% confidence interval about the ratio of the mean test value to mean reference value was
calculated for average AUEC response according to Locke’s method.
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PAR Mometasone Furoate 0.1% w/w Cream
UK/H/2276/01/DC
Results
The figure below shows an overlay of the mean corrected a* value chromameter scores vs.
chromameter reading times for all qualifying subjects for the test product when tested at the
ED50 dose duration, and with the reference product dosed at ED50, D1, and D2 dose durations,
and the untreated control site.
The results of the 94% confidence intervals and their widths are shown in the following table.
Safety
No serious adverse events were reported. One subject experienced 1 adverse event
(headache) which was deemed as not related to treatment.
Conclusion
The overall design of the programme with the initial study used to identify the doses for the
pivotal therapeutic equivalence study is according to current guidelines and is accepted. The
results of the therapeutic equivalence show that the test and reference products are
therapeutically equivalent.
Pharmacodynamics
No new pharmacodynamic data have been submitted and none are required for this
application.
Clinical efficacy
No new efficacy data have been submitted and none are required for this application.
Clinical safety
No new safety data have been submitted and none are required for this application.
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PAR Mometasone Furoate 0.1% w/w Cream
UK/H/2276/01/DC
No serious adverse events were reported. One subject experienced 1 adverse event
(headache) which was deemed as not related to treatment.
BENEFIT RISK ASSESSMENT
The benefit-risk ratio is considered favourable.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
Summary of Product Characteristics (SmPC)
The approved SmPC is consistent with that for the reference product and is acceptable.
Product Information Leaflet (PIL)
The final wording for the PIL is in line with the approved SmPC and is satisfactory.
Labelling
The labelling is satisfactory.
Expert Report
A satisfactory clinical over view is provided and has been prepared by an appropriately
qualified expert. The CV of the expert has been supplied.
CONCLUSIONS
The grounds for establishing the proposed product, Mometasone Furoate 0.1% w/w Cream,
as a generic version of the reference product, Elocon 0.1% w/w Cream (Schering Plough
Limited, UK), are considered adequate. The product literature is approved.
Sufficient clinical information has been submitted to support this application. All issues have
been adequately addressed but eh MAH. When used as indicated, Mometasone Furoate 0.1%
w/w Cream has a favourable benefit-risk ratio. The granting of a Marketing Authorisation
was therefore recommended.
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PAR Mometasone Furoate 0.1% w/w Cream
IV
UK/H/2276/01/DC
OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
The important quality characteristics of Mometasone Furoate 0.1% w/w Cream are welldefined 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.
No new preclinical data were submitted and none are required for an application of this type.
Therapeutic equivalence has been demonstrated between the applicant’s Mometasone
Furoate 0.1% w/w Cream and Elocon 0.1% cream (Schering-Plough Ltd UK).
No new or unexpected safety concerns arise from this application.
The SPC, PIL and labelling are satisfactory and consistent with that for the innovator
product.
The quality of the product is acceptable and no new preclinical or clinical safety concerns
have been identified. The therapeutic equivalence study supports the claim that the
applicant’s products and the innovator products are interchangeable. Extensive clinical
experience with mometasone furoate considered to have demonstrated the therapeutic value
of the compound. The risk benefit is, therefore, considered to be positive.
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PAR Mometasone Furoate 0.1% w/w Cream
UK/H/2276/01/DC
Module 6
STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY
Date
submitted
Application
type
Scope
Outcome
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