public assessment report decentralised procedure · (latanoprost and timolol) uk/h/3589/001/dc ......

PAR Latanoprost/ Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution UK/H/3589/001/DC

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Public Assessment Report

Decentralised Procedure

Lantanoprost /Timolol 50 micrograms/mL + 5 mg/mL Eye

Drops Solution

(latanoprost and timolol)

UK/H/3589/001/DC

UK licence no: PL 35638/0004

FDC Limited


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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/ Timolol 50 micrograms/mL + 5 mg/mL Eye Drops, Solution (PL 35638/0004). This licence was granted via the decentralised procedure (UK/H/3589/001/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). These eye drops contain two active ingredients: latanoprost and timolol. Latanoprost belongs to a group of medicines known as prostaglandin analogues. It increases the flow of fluid out of the eye. Timolol belongs to a group of medicines known as beta-blockers. It slows down the production of the fluid in the eye. These eye drops are used to treat open angle glaucoma or ocular hypertension. Both of these conditions are caused by too much pressure in the eye. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of using Latanoprost/ Timolol 50 micrograms/mL + 5mg/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 16 VI Overall conclusions Page 18 Module 6 Steps taken after initial procedure Page 19


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Module 1

Product Name

Latanoprost/ Timolol 50 micrograms /mL + 5 mg/mL Eye Drops Solution

Type of Application

Hybrid application, Article 10.3

Active Substance

Latanoprost and Timolol

Form

Eye Drops Solution

Strength

Latanoprost 50µg/ ml Timolol 5mg/ ml

MA Holder

FDC Ltd

RMS

UK

CMS

Germany, France, Italy and Spain

Procedure Number

UK/H/3589/001/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 Ltd for the medicinal product Latanoprost/Timolol 50 micrograms/mL + 5 mg/mL Eye Drops, Solution. The MA was authorised via a Decentralised Procedure (DCP), with the UK as Reference Member State (UK/H/3589/001/DC). After the national phase, a MA was granted in the UK on 23 July 2012 (PL 35638/0004). 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 XALACOM 50 mikrogram/mL Och 5 mg/mL ÖGONDROPPAR, LÖSNING has been registered in the EEA for more than 10 years; hence the period of data exclusivity has expired. XALACOM Eye Drops Solutions was first authorised to Pharmacia in Sweden on 15 December 2000 and subsequently in a number of other Member states including UK via the Mutual Recognition Procedure. A UK marketing authorisation for XALACOM Eye Drops Solution (Pharmacia Limited; PL 00032/0288) was granted on 20 July 2001. The licence subsequently underwent a change of ownership on 7 April 2010 to the current MAH Pfizer Limited (PL 00057/1056). Latanoprost is a prostaglandin F2α-analogue for the treatment of ocular hypertension and primary open angle glaucoma. 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 humor is hydrolysed by esterases during the passage through the cornea. Timolol is a potent non-subtype-selective β-adrenergic blocking agent, which does not have specific intrinsic sympathomimetic, direct myocardial depressant, membrane stabilising or local anaesthetic activity, widely used in the treatment of open-angle glaucoma and intraocular hypertension. Timolol binds to both β1- and β2-adrenergic receptors. β2-adrenergic receptors appear to be important for the activity on the iris-ciliary body. The proposed indications are:

Reduction of intraocular pressure (IOP), in patients with open angle glaucoma and ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.

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, in line with the “Note for Guidance on the Clinical Requirements for Locally Applied, Locally Acting Products Containing Known Constituents” CPWP/EWP/239/95 (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,


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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 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 and Timolol 5 mg/mL Eye Drops Solution

Name(s) of the active substance(s) (INN) Latanoprost and Timolol Pharmacotherapeutic classification (ATC code)

S01ED51 Ophthalmological-betablocking agents - timolol, combinations

Pharmaceutical form and strength(s) Eye Drops Solution Reference numbers for the Mutual Recognition Procedure UK/H/3589/001/DC

Reference Member State United Kingdom Member States concerned Germany, France, Italy and Spain Marketing Authorisation Number(s) PL 35638/0004 Name and address of the authorisation holder

FDC Pharma 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 (1) General Information Nomenclature INN: Latanoprost Chemical Name [1R-[1α(Z),2ß(R*),3α,5α]]-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-PGF2α-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 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. ACTIVE SUBSTANCE (2) General Information Nomenclature INN: Timolol maleate Chemical Name (S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3- yl)oxy]-2-propanol, hydrogen maleate Structure

Molecular formula: C17H28N4O7S Molecular Mass: 432.5 Description: White or almost white crystalline powder or colourless crystals. Solubility: Timolol is soluble in water and ethanol (96%). The active substance, timolol maleate, is the subject of a European Pharmacopoeia (Ph. Eur.) monograph. Manufacture All aspects of the manufacture and control of the active substance doxorubicin hydrochloride are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. MEDICINAL PRODUCT Description and Composition Latanoprost/ Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution is presented as a clear, colourless liquid. 1 mL of solution contains 50 micrograms latanoprost and 5 mg timolol ( as 6.8 mg timolol maleate).


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Other ingredients consist of the pharmaceutical excipients, sodium chloride, benzalkonium chloride, sodium dihydrogen phosphate monohydrate, disodium phosphate anhydrous, hydrochloric acid solution (pH adjustment), sodium hydroxide solution (pH adjustment) 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 XALACOM eye drops, solution (PL 00057/1056) currently authorised to Pfizer Limited.. Impurity profiles Comparative impurity data were provided for batches of the test reference products. The impurity profiles were found to be satisfactory. 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 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 yellow 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. 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.


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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 (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/ Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution and of the reference product, XALACOM Eye Drops Solution (PL 00057/1056) are equivalent. As satisfactory evidence of pharmaceutical equivalence to the reference 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. 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 and timolol 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/ Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution from a non-clinical point of view.


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III.3 CLINICAL ASPECTS Indications Reduction of intraocular pressure (IOP), in patients with open angle glaucoma and ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.

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. If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily. Paediatric population The safety and efficacy in children and adolescents has not yet been established. 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. Latanoprost Latanoprost is an isopropyl ester prodrug, which per se is inactive, but after hydrolysis by esterases in the cornea to the acid of latanoprost, becomes biologically active. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humor is hydrolysed during the passage through the cornea. After topical application in monkeys latanoprost is distributed primarily in the anterior segment, the conjunctiva and the eye lids. There is practically no metabolism of the acid of latanoprost in the eye. The main metabolism occurs in the liver. The main metabolites, the 1, 2-dinor and 1, 2, 3, 4- tetranor metabolites, exert no or only weak biological activity in animal studies and are excreted primarily in the urine. Timolol The maximum concentration of timolol in the aqueous humor is reached about 1 hour after topical administration of eye drops. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 ng/ml is reached 10-20 minutes after topical administration of one eye drop to each eye once daily (300 micrograms/day). The half life of timolol in plasma is about 6 hours. Timolol is extensively metabolised in the liver. The metabolites are excreted in the urine together with some unchanged Timolol. Latanoprost 50µg/ ml and Timolol 5mg/ ml Eye Drops Solution No pharmacokinetic interactions between latanoprost and timolol were observed although there was an approximate 2-fold increased concentration of the acid of latanoprost in aqueous humour 1-4 hours after administration of Latanoprost 50µg/ ml and Timolol 5mg/ ml Eye Drops Solution compared to monotherapy. Biowaiver Latanoprost/Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution is to be used as an aqueous ophthalmic solution and contains the same active substances, in the same


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concentrations, as the currently authorised reference product, XALACOM Eye Drops Solution (Pfizer Limited, UK). The physicochemical properties of Latanoprost/Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution, such as surface tension, osmolality, pH, viscosity have been studied and have been shown to be similar to those of the reference product XALACOM Eye Drops Solution (Pfizer Limited, UK).. Thus 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. 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 and timolol are well-known substances 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 / Timolol 50 micrograms/mL + 5 mg/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/Timolol 50 micrograms/mL + 5 mg/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 applicant’s product Latanoprost/Timolol 50 micrograms/mL + 5 mg/mL Eye Drops Solution has been demonstrated to be equivalent to the reference product XALACOM Eye Drops Solution (PL 00057/1056) authorised to Pfizer Limited in the UK on 20 July 2001. 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 applicant’s product Latanoprost/ Timolol 50 micrograms/mL + 5mg/mL Eye Drops Solution and the reference product XALACOM Eye Drops Solution (PL 00057/1056) are interchangeable. Extensive clinical experience with latanoprost is considered to have demonstrated the therapeutic value of the active substances. The benefit/risk ratio is considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report decentralised procedure · (latanoprost and timolol) uk/h/3589/001/dc ......

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