Public Assessment Report Scientific discussion Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml eye drops, solution (latanoprost/timolol maleate) NL/H/2935/001/DC Date: 12 January 2015 This module reflects the scientific discussion for the approval of Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml eye drops, solution. The procedure was finalised on 11 August 2014. For information on changes after this date please refer to the module Update.
I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml eye drops, solution from Apotex Europe B.V. The product is indicated for 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. A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a hybrid application claiming essential similarity with the innovator product Xalacom 50 microgram/ml + 5 mg/ml (NL License RVG 26592) which has been registered in the Netherlands since 12 September 2001 through procedure SE/H/0249/001/MR. In addition, reference is made to Xalacom authorisations in the individual member states (reference product). The concerned member states (CMS) involved in this procedure were Belgium, Czech Republic, Luxembourg, Poland and Spain. The marketing authorisation has been granted pursuant to Article 10(3) of Directive 2001/83/EC, a hybrid application, as bioequivalence cannot be demonstrated through bioavailability studies. II. QUALITY ASPECTS II.1 Introduction Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml is a clear, colourless aqueous solution of approximately ph 6.0 and 290 mosmols/l. 1 ml solution contains 50 micrograms latanoprost and 6.8 mg timolol maleate equivalent to 5 mg timolol. The solution is packed in a 5 ml white, translucent LDPE bottle and dropper tip, light yellow opaque HDPE screw cap, tamper evident LDPE overcap. Each bottle contains 2.5 ml eye drop solution. The excipients are: benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate monohydrate (E339), disodium phosphate anhydrous (E339), hydrochloric acid solution (for ph adjustment) (E507), sodium hydroxide solution (for ph adjustment) (E524), water for injections. II.2 Drug Substances Latanoprost The active substance latanoprost is an established active substance not described in the European Pharmacopoeia (Ph.Eur.). There is a monograph in the United States Pharmacopoeia (USP). Latanoprost is a clear to slightly opalescent, colourless to slightly amber oil which is practically insoluble in water and freely soluble in ethanol. Latanoprost has five chiral centres. The Active Substance Master File (ASMF) procedure is used for the active substance. The main objective of the ASMF procedure, commonly known as the European Drug Master File (EDMF) procedure, is to allow valuable confidential intellectual property or know-how of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the applicant or marketing authorisation holder (MAH) to take full responsibility for the medicinal product, the quality and quality control of the active substance. Competent Authorities/EMA thus have access to the complete information that is necessary to evaluate the suitability of the use of the active substance in the medicinal product. 2/7
Manufacturing process The described synthesis contains nine steps plus a purification step. No Class 1 solvents are used in the process. The active substance has been adequately characterized and acceptable specifications have been adopted for the starting materials, critical intermediates, solvents and reagents. Quality control of drug substance The specification of the MAH is acceptable in view of the route of synthesis and the various European guidelines. Batch analytical data demonstrating compliance with the drug substance specification have been provided for 21 full validation-scale batches. Stability of drug substance Stability data on the active substance have been provided for three revalidation scale batches stored at 5±3 C (36-48 months) and for four annual batches stored at 5±3 C (9-36 months). No out-ofspecification data were reported. Photostability testing has been performed in line with the Note for Guidance on the Photostability Testing of New Active Substances and Medicinal Products. The substance was demonstrated to be sensitive to light. Based on the provided data, a retest period of 3 years was granted, when protected from light. Timolol maleate Timolol maleate is an established active substance described in the Ph.Eur. It is a white or almost white crystalline powder, which is soluble in water, alcohol and practically insoluble in ether. No specific information about polymorphism has been found in literature. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The drug substance specification is in line with the Ph.Eur., with additional requirements for microbiological quality. The specification is acceptable in view of the route of synthesis and the various European guidelines. Batch analytical data demonstrating compliance with the drug substance specification have been provided for three full-scale batches. Stability of drug substance The active substance is stable for five years if stored under the stated conditions. Assessment thereof was part of granting the CEP and has been granted by the EDQM. II.3 Medicinal Product Pharmaceutical development The development of the product has been described, the choice of excipients is justified and their functions explained. During the main development studies performed the concentrations of the excipients were varied to come to a formulation that is equivalent with the originator product. The excipients are well known for this type of product as well as the packaging material/components. Two sterilisation methods for the packaging components have been used. The sterilisation process of the medicinal product, sterile filtration, has also been justified. A comparison of the relevant physicochemical parameters (e.g. droplet volume, ph, viscosity, osmolality, density, surface tension, buffering capacity) has been performed between test and reference product, demonstrating satisfactory results. No clinical studies were performed. A waiver can be granted based on the proven pharmaceutical and physicochemical equivalence. The pharmaceutical development of the product has been adequately performed. Manufacturing process 3/7
The manufacturing process consists of a non-aseptic process of weighing and mixing. Subsequent filtration, filling and sealing of the containers are aseptic processes that occur in sanitized isolators. The manufacturing process has been adequately validated according to relevant European guidelines. Appropriate in-process controls are in place. Process validation data on the product have been presented for three full-scale batches, as the product is manufactured using non-standard manufacturing techniques. Microbiological attributes The results show that the product is effectively preserved and meets Ph.Eur. 5.1.3. Criteria A at all concentrations of benzalkonium chloride tested: 20%, 40%, 60%, 80% and 100% of the label claim. Container closure integrity has been demonstrated. Control of excipients The excipients comply with Ph. Eur. or the British Pharmacopoeia. These specifications are acceptable. Quality control of drug product The product specification includes tests for appearance, identity and assay of active substances and preservative, ph, colour, osmolality, deliverable volume, particulate matter, degradation, sterility. At end of shelf-life also weight loss and seal integrity are proposed tests. The release and shelf-life limits are identical, except for higher limits of degradation products at end of shelf-life. The specifications are acceptable. The analytical methods have been adequately described and validated. Batch analytical data from the proposed production site have been provided on three full-scale batches, demonstrating compliance with the release specification. Stability of drug product Stability data on the product has been provided for three full-scale batches stored at 5±3 C (18 months) and 25 C/40% RH (6 months). The conditions used in the stability studies are according to the ICH stability guideline. The batches were stored in the proposed commercial packaging (5 ml white LDPE bottles with white LDPE droppers and light yellow HDPE caps, containing 2.5 ml solution). At long term conditions (5 C), at 18 months, no specific trends or changes are seen for any of the parameters. Therefore the proposed storage time (2 years) is acceptable. The proposed storage condition (store unopened bottle in the refrigerator) is justified. Photostability testing showed that the bottle should be kept in the outer carton in order to protect from light. In-use studies are performed at 4 and 10 weeks of storage. Drops were removed from the bottle every day (2 drops in the first week, 1 drop for the remaining 9 weeks). These condition is to mimic the use of the product (one drop per day per eye), assuming that one eye is affected. Results showed compliance to the acceptance criteria at 4 and 10 weeks. The proposed in use storage period and condition (28 days at room temperature up to 25 C) is accepted. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substances and finished product. The equivalence between Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml and Xalacom 50 microgram/ml + 5 mg/ml has sufficiently demonstrated on pharmaceutical and physicochemical grounds. The following post-approval commitments were made: The MAH will verify the potency of its Latanoprost Primary Reference Standard against the USP Latanoprost Reference Standard when the latter will become available. The MAH committed that any extension beyond the current acceptable hold time of 31 hours will be submitted via appropriate variation post approval. 4/7
III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Latanoprost/Timolol Apotex is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.2 Discussion on the non-clinical aspects This product is a hybrid formulation of Xalacom, which is available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-todate and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Latanoprost and timolol are well-known active substances with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. IV.2 Pharmacokinetics According to the Guideline on Investigation of Bioequivalence, a waiver of clinical studies for locally acting locally applied drug products is acceptable in the case of solutions, e.g. eye drops. For Latanoprost/Timolol Apotex eye drops, solution the requirements are fulfilled: same type of (aqueous) solution, same concentration of the same active substance, method and means of administration is the same, same concentration of benzalkonium chloride and same composition of the excipients. Pharmaceutical and physicochemical equivalence is proven in the in vitro study, which showed that test and reference product have a comparable droplet volume, ph, viscosity, osmolality, density, surface tension and buffering capacity. Thus the requirements are fulfilled for locally applied, locallyacting products under the EU CPMP guideline on bioequivalence (CPMP/EWP/239/95). Latanoprost/Timolol Apotex 50 micrograms/ml + 5 mg/ml eye drops, solution may be considered as therapeutic equivalent, with the same efficacy/safety profile as known for the active substance of the reference medicinal product. The current product can be used instead of its reference product. IV.3 Risk Management Plan The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Latanoprost/Timolol Apotex. - Summary table of safety concerns as approved in RMP Important identified risks Iris Pigmentation, Punctate Keratitis BAK-related corneal toxicity Important potential risks Systemic beta-blocking effects (decreased inotropic and chronotropic cardiac function, hypotension, 5/7
C bronchospasms, hypoglycaemia) Choroidal Effusion/detachment Reactivation of Corneal infiltrates Reactivation of previous infective ocular disease Off-label use (cosmetic use for the purpose of stimulating eyelash growth) Missing information Exposure in pregnancy and lactation Exposure in paediatric patients The member states agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information. IV.4 Discussion on the clinical aspects For this authorisation, reference is made to the clinical studies and experience with the innovator product Xalacom. No new clinical studies were conducted. The MAH demonstrated pharmaceutical equivalence to the reference product based on in vitro data. Risk management is adequately addressed. This hybrid medicinal product can be used instead of the reference product. V. USER CONSULTATION 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 test consisted of a pilot test with two participants, followed by two rounds with 10 participants each. The main objective of the readability testing has been examined, i.e. well-finding and well understanding. The key messages for the safe use of Latanoprost/Timolol Apotex eye drops were identified and they were included in the questionnaire. The results show that the tested package leaflet is in line with the readability requirements. No revisions were deemed necessary. It was demonstrated that the leaflet is easy to read and understandable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml eye drops, solution has a proven chemicalpharmaceutical quality and is a hybrid form of Xalacom 50 microgram/ml + 5 mg/ml eye drops, solution. Xalacom is a well-known medicinal product with an established favourable efficacy and safety profile As Latanoprost/Timolol Apotex is a product for ocular use (eye drops) intended to act without systemic absorption, with the same excipients used in the reference product, it is exempted for bioequivalence study. The Board followed the advice of the assessors. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Latanoprost/Timolol Apotex 50 microgram/ml + 5 mg/ml with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 11 August 2014. 6/7
STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached 7/7