PAR Latanoprost 50 micrograms/mL Eye Drops Solution UK/H/4549/001/DC

Public Assessment Report

Decentralised Procedure

Latanoprost 50 micrograms/mL Eye Drops Solution

(latanoprost)

UK/H/4549/001/DC

UK licence no: PL 35638/0003

FDC Pharma

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LAY SUMMARY
On 23 July 2012, the Medicines and Healthcare products Regulatory Agency (MHRA)
granted FDC Pharma a Marketing Authorisation (licence) for the medicinal product
Latanoprost 50 micrograms/mL Eye Drops, Solution (PL 35638/0003). This licence was
granted via the decentralised procedure (UK/H/4549/001/DC), with the UK as the
Reference Member State (RMS) and Germany, France, Italy and Spain as Concerned
Member States (CMSs).

This is a prescription-only medicine (POM) and is indicated to treat conditions known as

open angle glaucoma and ocular hypertension in adults. Both of these conditions are linked
with an increase in the pressure within the eye, which eventually affect the eyesight.
Latanoprost is also used to treat increased eye pressure and glaucoma in all ages of
children and babies.

Latanoprost belongs to a group of medicines known as prostaglandin analogues. It works

by increasing the natural outflow of fluid from inside the eye into the bloodstream.

No new or unexpected safety concerns arose from this application and it was therefore
judged that the benefits of using Latanoprost 50 micrograms/mL Eye Drops, Solution
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 6

Module 4: Labelling Page 7

Module 5: Scientific Discussion Page 10

I Introduction Page 10
II About the Product Page 11
III Quality aspects Page 12
IV Non-clinical aspects Page 15
V Clinical aspects Page 15
VI Overall conclusions Page 17

Module 6 Steps taken after initial procedure Page 18

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Module 1

Product Name Latanoprost 50 micrograms /mL Eye Drops, Solution

Type of Application Hybrid application, Article 10.3

Active Substance Latanoprost

Form Eye Drops Solution

Strength 50 microgram/mL

MA Holder FDC Pharma

RMS UK

CMS Germany, France, Italy and Spain

Procedure Number UK/H/4549/001/DC

End of Procedure 26 April 2012

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Module 2
Summary of Product Characteristics
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics
(SmPC) and Patient Information Leaflets (PIL) for products granted Marketing
Authorisations at a national level are available on the MHRA website.

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Module 3
PATIENT INFORMATION LEAFLET
In accordance with Directive 2010/84/EU the Summaries of Product Characteristics
(SmPC) and Patient Information Leaflets (PIL) for products granted Marketing
Authorisations at a national level are available on the MHRA website.

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Module 4
Labelling

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Module 5
Scientific discussion during initial procedure
I INTRODUCTION
On 26 April 2012, Germany, France, Italy and Spain and the UK agreed to grant a
Marketing Authorisation (MA) to FDC Pharma for the medicinal product Latanoprost
50 micrograms/mL Eye Drops, Solution. The MA was granted via a Decentralised
Procedure (DCP), with the UK as Reference Member State (UK/H/4549/001/DC). After
the national phase, a MA was granted in the UK on 23 July 2012 (PL 35638/0003).

This application was made under Article 10.3 of Directive 2001/83/EC, as amended, as a
hybrid application. The reference medicinal product for this application is Xalatan 0.005%
Eye Drops Solution (PL 00057/1057) authorised to Pfizer Limited in the UK on 16
December 1996.The reference product has been registered in the EEA for more than 10
years; hence the period of data exclusivity has expired.

The active substance latanoprost, is a prostaglandin F2-analogue, is a selective prostanoid

FP receptor agonist which reduces the intraocular pressure by increasing the outflow of
aqueous humour and is indicated in the treatment of ocular hypertension (OH) and primary
open angle glaucoma (POAG). Latanoprost is an isopropyl ester prodrug, which is inactive
but becomes biologically active after hydrolysis to the acid of latanoprost. The prodrug is
well absorbed through the cornea and all of the drug that enters the aqueous humour is
hydrolysed by esterases during the passage through the cornea.

Proposed indications are:

Reduction of elevated intraocular pressure in patients with open angle

glaucoma and ocular hypertension.
Reduction of elevated intraocular pressure in paediatric patients with
elevated intraocular pressure and paediatric glaucoma.

No new non-clinical or clinical studies were conducted, which is acceptable given that this
is a hybrid application cross-referring to a product that has been licensed for over 10 years.
No therapeutic studies have been performed and none are required for this application,
conforming to Guideline CPWP/EWP/239/95. Latanoprost 50 micrograms/mL Eye Drops,
Solution is an ophthalmic solution and was developed to be identical to the reference
product Xalatan 0.005%w/v Eye Drops Solution with respect to its qualitative and
composition and physiochemical properties (see Clinical Aspects).

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 and
assembly of these products. Evidence of compliance with GMP has been provided for the
named manufacturing and assembly sites. 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.

For manufacturing sites outside the community, the RMS has accepted copies of current
GMP certificates or 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

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territories) as certification that acceptable standards of GMP are in place at those non-
Community sites.

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 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
risk minimisation have not been identified, 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 substance is well established.

The Marketing Authorisation Holder has provided adequate justification for not submitting
an Environmental Risk Assessment (ERA). This was an application for a generic
medicinal product and there is no reason to conclude that the marketing of this product will
change the overall use pattern of the existing market.

II. ABOUT THE PRODUCT

Name of the product in the Reference Member State Latanoprost 50 micrograms/mL Eye Drops
Solution

Name(s) of the active substance(s) (INN) Latanoprost

Pharmacotherapeutic classification S01 EE01
(ATC code) Prostaglandin analogues
Pharmaceutical form and strength(s) Eye Drops Solution
Reference numbers for the Mutual Recognition Procedure UK/H/4549/001/DC

Reference Member State United Kingdom

Member States concerned Germany, France, Italy and Spain
Marketing Authorisation Number(s) PL 35638/0003
Name and address of the FDC Pharma
authorisation holder Unit 6 Fulcrum
Solent Business Park, Solent Way,
Whitely, Fareham,
Hampshire
PO15 7FE
United Kingdom

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III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 QUALITY ASPECTS

ACTIVE SUBSTANCE

General Information
Nomenclature
INN: Latanoprost

Chemical Name [1R-[1(Z),2(R*),3,5]]-7-[3,5-Dihydroxy-2-(3-hydroxy-5-

phenylpentyl)cyclopentyl]-5-heptenoic acid 1-methylethyl ester.

13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2-isopropylester.

Isopropyl-(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy- 5-
phenylpentyl]cyclopentyl]-5-heptenoate

Structure

Molecular formula: C26H40O5

Molecular Mass: 432.59

Description: Pale yellow to yellow viscous oil

Solubility: Practically insoluble in water, freely soluble in chloroform, acetone and alcohol

The active substance, latanoprost, is currently not the subject of a European

Pharmacopoeia (Ph. Eur.) or British Pharmacopoeia (BP) monograph.

Manufacture
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.

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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.

MEDICINAL PRODUCT
Description and Composition
Latanoprost 50 micrograms/mL Eye Drops Solution is presented as a clear, colourless
liquid. 1 mL of solution contains 50 micrograms latanoprost; one drop contains
approximately 1.5 micrograms of latanoprost.

Other ingredients consist of the pharmaceutical excipients, benzalkonium chloride, sodium

chloride, sodium dihydrogen phosphate monohydrate, disodium phosphate anhydrous and
water for injections.

All excipients used with the exception of sodium dihydrogen phosphate (which meets the
requirements of the British Pharmacopeia) comply with their respective European
Pharmacopeial monograph. Satisfactory certificates of analysis have been provided for all
excipients. Appropriate justification for the inclusion of each excipient has been provided.
The applicant has provided a declaration to confirm that there are no materials of human or
animal origin contained in the product, or used in the manufacturing process. Furthermore,
no genetically modified organisms are used in the manufacture of the excipients.

There are no novel excipients used.

Pharmaceutical Development
Details of the pharmaceutical development of the medicinal product have been supplied
and are satisfactory. The objective was to develop robust, stable ophthalmic preparation
that is pharmacologically equivalent and comparable in performance to the to the reference
product Xalatan 0.005% Eye Drops Solution (PL 00057/1057) authorised to Pfizer Limited
in the UK on 16 December 1996.

Impurity profiles
Comparative impurity data were provided for the test and reference products. The impurity
profiles were found to be similar, with all impurities within the specification limits.

Manufacture
A description and flow-chart of the manufacturing process 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. The validation
data demonstrated consistency of the manufacturing process.

Finished Product Specification

The finished product specifications are provided for both release and shelf-life and are acceptable.
Test methods have been described and have been validated, as appropriate. The batch analysis

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results show that the finished product meets the specification proposed. Certificates of Analysis
have been provided for any working standards used.

Container Closure System

The finished product is licensed for marketing in low density polyethylene (LDPE) 5 mL bottles
with an insert cap assembly comprising of a turquoise coloured screw cap over a LDPE nozzle
with tamper evident LDPE dustcover sealing the bottle cap. Each bottle contains 2.5 mL eye
drops solution corresponding to approximately 80 drops of solution. The bottles are packaged
with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 1 x 2.5mL,
3 x 2.5 mL and 6 x 2.5 mL.

Satisfactory specifications and Certificates of Analysis for all packaging components used
have been provided. All primary product packaging complies with EU legislation,
Directive 2002/72/EC (as amended); the LDPE bottles comply with Ph Eur requirements
and are suitable for contact with eye drop solution preparations.

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 (before first opening) and 4 weeks (after first opening) has been set.
The storage conditions for the unopened product are, Store in a refrigerator (2oC -8oC)
and Keep the bottle in the outer carton in order to protect from light. After the first
opening of the bottle Do not store above 25oC and use within four weeks have been set. .

Bioequivalence/bioavailability Study
As the product provides local therapeutic activity, investigation of
bioequivalence/bioavailability is not necessary for this product and none has been provided
(see comments under Clinical Aspects). Sufficient evidence was provided to demonstrate
that the physicochemical properties of Latanoprost 50 micrograms/mL Eye Drops Solution
and of the reference product, Xalatan 0.005% Eye Drops Solution (PL 00057/1057) are
equivalent. As satisfactory evidence of pharmaceutical equivalence to the innovator
product was provided, no further non-clinical or clinical studies were required or provided.

Quality Overall Summary

A satisfactory quality overview is provided and has been prepared by an appropriately qualified
expert. The curriculum vitae of the expert has been provided.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and

Labelling
The SmPC, PIL and labelling are acceptable from a pharmaceutical perspective. Colour
mock-ups of the labelling and PIL have been provided.

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 show that the patients/users are able to act upon the information that is contains.
The text of the SmPC, PIL and label is satisfactory and consistent with that for the
reference product.

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Conclusion
From a pharmaceutical point of view, it is recommended that a Marketing Authorisation is
granted for this application.

III.2 Non-clinical aspects

The pharmacodynamic, pharmacokinetic and toxicological properties of latanoprost are
well-known. Therefore, no further studies were required for this application and the
applicant has provided none.

An acceptable justification for the lack of an environmental risk assessment has been
submitted. It is expected that sales of this product will replace those of marketed product
and that no increase in environmental exposure to the active substance is likely The non-
clinical overview was written by a suitably qualified person and is satisfactory. The
curriculum vitae of the expert has been provided.

There are no objections to approval of Latanoprost 50 micrograms/mL Eye Drops Solution

from a non-clinical point of view.

III.3 Clinical aspects

Indications
Reduction of elevated intraocular pressure in patients with open angle glaucoma
and ocular hypertension.

Reduction of elevated intraocular pressure in paediatric patients with elevated

intraocular pressure and paediatric glaucoma.

The proposed indications are consistent with the UK reference product.

Posology and Method of Administration

Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is
obtained if Latanoprost 50 micrograms/mL Eye Drops Solution is administered in the
evening.

Full details concerning the posology are provided in the SmPC. The posology is consistent
with that for the reference product and is satisfactory.

Clinical Pharmacology
Pharmacokinetics
No new data have been submitted and none are required for an application of this type.

Biowaiver
In accordance with the Guideline on the Investigation of Bioequivalence
(CPMP/EWP/QWP/1401/98 Rev.1 Corr**) the applicant is not required to submit a
therapeutic equivalence study.

Pharmacodynamics
No new data have been submitted and none are required for an application of this type.

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Clinical efficacy
No new data have been submitted and none are required for an application of this type.

Clinical safety
No new safety data have been submitted or are required for this hybrid application. As
latanoprost is a well-known substance with an acceptable adverse event profile, this is
satisfactory.

Expert Report
A satisfactory clinical overview is provided, and has been prepared by an appropriately
qualified physician. The curriculum vitae of the expert has been provided.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),

Labels
The SmPC and PIL are acceptable from a clinical perspective, and consistent with those
for the reference product. The labelling is acceptable and in-line with current requirements.

Marketing Authorisation Application (MAA) form

The MAA form is satisfactory.

Conclusion
There are no objections to the approval of Latanoprost 50 micrograms/mL Eye Drops
Solution from a clinical point of view.

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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

QUALITY
The important quality characteristics of Latanoprost 50 micrograms/mL Eye Drops
Solution 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 an application of this
type.

EFFICACY
The applicants product Latanoprost 50 micrograms/mL Eye Drops Solution has been
demonstrated to be equivalent to the reference product Xalatan 0.005% Eye Drops
Solution (PL 00057/1057) authorised to Pfizer Limited in the UK on 16 December 1996.

No new or unexpected safety concerns arose from this application.

PRODUCT LITERATURE
The SmPCs and PILs are acceptable and are consistent with those for the reference
product. The labelling is acceptable and in-line with current requirements.

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 results show that
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.

BENEFIT/RISK ASSESSMENT
The quality of the product is acceptable and no new non-clinical or clinical safety concerns
have been identified. The qualitative and quantitative assessment supports the claim that
the applicants product Latanoprost 50 micrograms/mL Eye Drops Solution and the
reference product Xalatan 0.005% Eye Drops Solution (PL 00057/1057) are
interchangeable. Extensive clinical experience with latanoprost is considered to have
demonstrated the therapeutic value of the active substance. The benefit/risk ratio is
considered to be positive.

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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date Application Scope Outcome

submitted type

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