Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure RMS Public Assessment Report Latanoprost Malcosa 0,005% Xalaprost 0,005% Laxatan 0,005% Pharmecol 0.005% DE/H/1999/001/DC DE/H/2281/001/DC DE/H/2282/001/DC DE/H/2382/001/DC Applicant: Malcosa Ltd. Reference Member State DE Date of this report: 06.12.2010 The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/30 CONTENTS ADMINISTRATIVE INFORMATION .............................................................................................. 3 I. RECOMMENDATION ................................................................................................................ 4 II. EXECUTIVE SUMMARY....................................................................................................... 4 II.1 Problem statement..................................................................................................................... 4 II.2 About the product ..................................................................................................................... 4 II.3 General comments on the submitted dossier .......................................................................... 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................... 6 III.1 Quality aspects....................................................................................................................... 6 III.2 Nonclinical aspects ................................................................................................................ 7 III.3 Clinical aspects ...................................................................................................................... 7 IV. BENEFIT RISK ASSESSMENT ........................................................................................... 30 V. Package Leaflet (PL)/Assessment of User Testing ............................................................... 30 2/30 ADMINISTRATIVE INFORMATION a) Latanoprost Malcosa 0,005% Proposed name of the medicinal b) Xalaprost 0,005% product in the RMS c) Laxatan 0,005% d) Pharmecol 0.005% INN (or common name) of the active Latanoprost substance(s): Pharmaco-therapeutic group S01EE01 (ATC Code): Pharmaceutical form(s) and Eye drops, solution, 50 microgram/ml strength(s): a) DE/H/1999/001/DC Reference Number for the b) DE/H/2281/001/DC Decentralised Procedure c) DE/H/2282/001/DC d) DE/H/2382/001/DC Reference Member State: DE a) BG, CY, EL, ES, IT, PL, PT, RO b) BG, CZ, HU, PL, RO, SK Member States concerned: c) AT, UK d) BG Malcosa Ltd. Acropolis Tower, 66 Acropolis avenue Applicant (name and address) 2012 Strovolos - Nicosia Cyprus Malcosa Ltd. Names and addresses of Acropolis Tower, 66 Acropolis avenue manufacturers responsible for batch release in the EEA 2012 Strovolos - Nicosia Cyprus 3/30 A) RECOMMENDATION Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMS on quality, safety and efficacy, the RMS considers that the application for Latanoprost Malcosa 0,005%, in the treatment of Reduction of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension, is approvable as satisfactory responses are given and the applicant committed to perform a number of post authorisation follow- up measures. EXECUTIVE SUMMARY a.1 Problem statement The submitted documentation is in accordance with a "generic application". The application refers to an essential similar original product granted for more than 10 years in the Community according to Directive 2001/83/EC Article 10(1). This mutual recognition application concerns a generic version of Latanoprost. Latanoprost Eye drops solution of 0.005% is registered in most of the European countries under the brand name of Xalatan® by Pfizer. The data protection period is already expired and reference has been made to the non-clinical and clinical documentation of the reference product. The Marketing Authorization for Xalatan 0.005% eye drops solution was first granted for the UK market on December 16, 1996. ® The product Latanoprost was developed as a generic alternative to Xalatan ophthalmic solution (Latanoprost 50μg/ml, Pfizer) with minor changes in the composition (see confidential ANNEX). The product is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolarity of approximately 270mOsmol/kg. Each millilitre of Latanoprost finished product contains 50 micrograms of Latanoprost. Benzalkonium chloride, 0.02 % is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous and water for injection. The present Product License application is therefore submitted under Directive 2001/83/EC, Article 10.1 (a) (iii) in cross-reference to the pharmaco-toxicological and clinical data supporting the brand leader Xalatan® ophthalmic solution 50 μg/ml a.2 About the product The active substance latanoprost, a prostaglandin F2analogue, is a selective prostanoid FP receptor agonist which reduces the intraocular pressure by increasing the outflow of aqueous humour. Reduction of the intraocular pressure in man starts about three to four hours after administration and maximum effect is reached after eight to twelve hours. Pressure reduction is maintained for at least 24 hours. 4/30 Latanoprost Malcosa is indicated in the treatment of elevated intraocular pressure in patients with open angle glaucoma and ocular hypertension. The recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Xalatan is administered in the evening. A possible risk management strategy is not yet established, but will be developed by the company. a.3 General comments on the submitted dossier Legal basis: The application of Latanoprost Malcosa is submitted under Directive 2001/83/EC, Article 10.1 (a) (iii) in cross-reference to the pharmaco-toxicological and clinical data supporting the originator Xalatan® ophthalmic solution 50 μg/ml. The type of marketing authorisation application incl. reference to legal basis of the application is appropriate. The Reference medicinal product XALATAN 0,005% Colirio en solución PFIZER, S.A has been authorized for the Spainish market on 23/12/1997 under the Marketing authorisation number: 61.756. The SmPC of the originator is also used for Latanoprost Malcosa. Essential Similarity: Eye drops solutions of the Reference products from the Korean and the Dutch market and the Latanoprost Malcosa have been compared with respect to the physicochemical parameters. Samples tested were as follows: Product Strength Country Lot No / Expiry Xalatan® Eye drops solution Korea ND0115 / 03/2009 0.005% Xalatan® Eye drops solution Holland NH0379 / 08/2009 0.005% Latanoprost Malcosa Eye drops solution 7001/ 02/2007 0.005% The results obtained for the assay of Latanoprost in the three formulations under comparison were well within the ±5% limit of the labeled claim. In addition, comparisons of the impurity profile that Xalatan has a relative high percentage of 5,6 trans-Latanoprost but more or less the same profile on the rest of the impurities. Conclusion The comparison of all the above described tests adequately supports the pharmaceutical equivalence of the Latanoprost Malcosa 0.005% Eye drops solution and Xalatan 0.005% Eye drops solution (composition of Latanoprost Malcosa - see confidential part). The applicant summaried the grounds and evidence used for demonstrating that the constituents of Latanoprost Malcosa have a well- established use with an acceptable level of safety and efficacy. Risk management plan: A qualified person responsible for pharmacovigilance activities (QPRP) has been appointed by the applicant to ensure permanent and continous availability for pharmacovigilance activities. A system is in place to ensure the surveillance of Latanoprost Malcosa worldwide. Indication and posology: The proposed indication and posology is in line with the SmPC of the originator. Paediatric indication: A paediatric development could not be recommended at the moment, because the originator has also no paediatric indication. 5/30 a.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The Qualified Person of., the manufacturer located in the EEA and responsible for batch release, declares that the active substance manufacturer operates in compliance with the detailed guidelines on good manufacturing practice for starting materials. The drug product is manufactured as a sterile ophthalmic solution. The manufacture of the formulation and primary packaging takes place at A copy of the GMP certificate has been provided. Additionally a copy of the GMP certificate issued by the competent Polish Inspection Service, dated 12.05.2008, has been provided. The Main Pharmaceutical Inspector states that the manufacturing conditions for Latanoprost 0.005% eye drops at the manufacturing site , comply with the requirements of Good Manufacturing Practice. The RMS has accepted this copy as certification that acceptable standards of GMP are in place at this site outside the Community. Secondary packaging takes place at Batch release is performed by The RMS has accepted copies of the current manufacturer authorisation and the GMP certificate issued by inspection services of the competent authority of