Decentralised Procedure Public Assessment Report Fenticonazol Bailleul 20 mg/g Creme Fenticonazole nitrate DE/H/5048/001/DC Date: 23.08.2017 Applicant: LABORATOIRES BAILLEUL S.A Reference Member State DE TABLE OF CONTENTS I. INTRODUCTION ............................................................................................................. 4 II. EXECUTIVE SUMMARY ................................................................................................ 4 II.1 Problem statement ............................................................................................................. 4 II.2 About the product.............................................................................................................. 4 II.3 General comments on the submitted dossier ...................................................................... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles ... 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................... 5 III.1 Quality aspects................................................................................................................... 5 III.2 Non-clinical aspects............................................................................................................ 5 III.3 Clinical aspects .................................................................................................................. 6 IV. BENEFIT RISK ASSESSMENT ..................................................................................... 10 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Fenticonazol Bailleul 20 mg/g Creme product in the RMS Name of the drug substance (INN Fenticonazole nitrate name): Pharmaco-therapeutic group Antifungals for topical use; Imidazole and triazole (ATC Code): derivatives (D01AC12) Pharmaceutical form(s) and Cream, 20 mg/g strength(s): Reference Number(s) for the DE/H/5048/001/DC Decentralised Procedure (withdrawal of DE/H/5048/002/DC) Reference Member State: DE Concerned Member States: FR, LU Applicant (name and address) LABORATOIRES BAILLEUL S.A 10 Rue Nicolas Adames L1114 - Luxembourg LABORATOIRES CHEMINEAU Names and addresses of all proposed 93 Route de Monnaie, manufacturer(s) responsible for 37210 VOUVRAY batch release in the EEA FRANCE Fenticonazol Bailleul 20 mg/g Crème, DE/H/5048/001/DC Public AR 3/10 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Fenticonazol Bailleul 20 mg/g Creme is used in adults and adolescents 12 years of age and above for: 1. Candidiasis The candidiasis encountered in human clinical practice is usually due to Candida albicans. However, the identification of Candida on the skin may not in itself be an indication. Treatment: - intertrigo, especially genital-crural, anal, and perianal, - angular cheilitis. In some cases, it is advisable to treat the gastrointestinal tract simultaneously. Adjunctive treatment for onychia and paronychia. 2. Dermatophytosis Treatment: - dermatophytosis of the glabrous skin - genital and crural intertrigo - intertrigo of the toes 3. Tinea versicolor is approved. II. EXECUTIVE SUMMARY II.1 Problem statement Fenticonazol Bailleul 20 mg/g Creme has been developed by Laboratoires BAILLEUL with the objective to be essentially similar to the Reference products Lomexin® 2% cream marketed by Laboratoires EFFIK in France and various European countries. The legal basis of the Marketing authorisation application is under Article 10(3) of Directive 2001/83/EC, as amended i.e., a hybrid application for an essentially similar generic medicinal product. II.2 About the product Fenticonazol Bailleul 20 mg/g Creme is a medicinal product containing 2% m/m of fenticonazole nitrate. It is indicated for the treatment of fungal diseases of the skin or mucosa, especially Pityriasis versicolor and tinea corporis and other infections by dermatophytes, yeasts and other fungi. The active ingredient fenticonazole nitrate is an imidazole derivative belonging to the Pharmacotherapeutic group of: DERMATOLOGICALS - Antifungals for topical use - Imidazole and triazole derivatives ATC Code: D01AC12. The compound exerts its unique antimycotic mechanism of action in the following three ways: (i) inhibition of the secretion of protease acid by Candida albicans (ii) damage to the cytoplasmic membrane; and (iii) by blocking cytochrome oxidases and peroxidases. Imidazole derivatives control fungal infections by damaging the fungal cell membrane via inhibition of the fungal P450 isozyme, which is required to convert lanosterol to ergosterol, an essential component of fungal cell membrane synthesis. Fenticonazole has also been shown to exhibit antibacterial action, with a spectrum of activity that includes bacteria commonly associated with superinfected fungal skin and vaginal infections, and antiparasitic action against the protozoan Trichomonas vaginalis. II.3 General comments on the submitted dossier The legal basis of the Marketing authorisation application is under Article 10.3 of Directive 2001/83/EC, as amended i.e., a hybrid application for an essentially similar generic medicinal product. The active substance fenticonazole nitrate is not considered as a new active substance. Fenticonazol Bailleul 20 mg/g Crème, DE/H/5048/001/DC Public AR 4/10 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 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. A valid GMP certificate of the drug substance manufacturing site based on an inspection in June 2016 and a QP declaration are provided. The CEP by the EDQM as can be seen on the EDQM certification database. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance is a compendia substance. Drug substance specifications and batch analysis data for the drug substance supplier and the drug product manufacturer for the cream are provided. Stability data over 48 months at long-term conditions and 6 months at accelerated conditions support the re-test period of 48 months. Drug product (2% cream) The drug product is a cream containing 2 g fenticonazole nitrate in 100 g. The cream is packaged in epoxy-lined blind-end aluminium tubes with a polypropylene screw cap. A comparative study of the applied product and the reference product was performed showing that the particle size distribution for both products is similar from a granulometric stand point. The manufacturing process including flow chart and in-process controls are adequately described. Process validation data for one pilot and two production batches are provided. A process validation scheme for three production batches of the highest strengths is presented. Each of the excipients except the Polyglycolic ester of fatty acid complies with respective Ph. Eur. or BP monographs. For Polyglycolic ester of fatty acid, an adequate in-house monograph is documented. The release and shelf life specifications are appropriate for an adequate control of the drug product. The analytical control methods are described and are validated in accordance with ICH validation guideline. Batch analysis data are given showing compliance with set specifications. Based on the provided stability data a shelf life of 9 months, if stored below 25°C, is accepted. III.2 Non-clinical aspects There are no objections to approval of Fenticonazol Bailleul 20 mg/g Creme from a non-clinical point of view. Environmental Risk Assessment (ERA) Summary of main study results Substance: fenticonazole CAS-number (if available): Phase I Calculation Value Unit Conclusion PEC surface water , default or refined 0.0153 g/L > 0.01 threshold (Y) (e.g. prevalence, literature) Other concerns (e.g. chemical class) Endocrine Active (Y) Substance The calculated PEC surfacewater value is above 0.01 μg/l, therefore a detailed Phase II ERA is deemed necessary. The applicant agreed to perform a detailed and tailored ERA according to the principles of the EMA guideline EMEA/CHMP/SWP/4447/00 and in consideration of the specific endocrine mode of action of the active substance fenticonazole. The RMS acknowledges the recalculation of the PEC for surfacewater and the applicant’s commitment to conduct a tailored ERA. Fenticonazol Bailleul 20 mg/g Crème, DE/H/5048/001/DC Public AR 5/10 III.3 Clinical aspects Pharmacokinetics N/A Pharmacodynamics Fenticonazole exerts its unique antimycotic mechanism of action in the following three ways: 1. inhibition of the secretion of protease acid by Candida albicans, 2. damage to the cytoplasmic membrane; and 3. blocking cytochrome oxidases and peroxidises. Imidazole derivatives control fungal infections by damaging the fungal cell membrane via inhibition of the fungal P450 isozyme, which is required to convert lanosterol to ergosterol, an essential component of fungal cell membrane synthesis. Fenticonazole has also been shown to exhibit antibacterial action, with a spectrum of activity that includes bacteria commonly associated with superinfected fungal skin and vaginal infections, and antiparasitic action against the protozoan Trichomonas vaginalis. Therefore, fenticonazole may be an ideal topical alternative to multi-agent treatment of mixed infections involving mycotic, bacterial, dermatophyte and/or Trichomonas spp. Open-label clinical studies