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 for topical use; and (ATC Code): derivatives (D01AC12) Pharmaceutical form(s) and , 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

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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 . 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 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 , 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.

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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.

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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 show that fenticonazole, in different pharmaceutical preparations administered once or twice daily, is effective in the treatment of superficial mycoses of the skin. In particular, fenticonazole is very effective (often with 100% of patients achieving a negative mycological assay) in pityriasis versicolor and candidiasis. For example, a large (n = 760) study showed fenticonazole 2% cream, spray or powder to be associated with a mycological response in 100% of patients with pityriasis versicolor, 96.3% of those with tinea infections and 95.2% of patients with Candida infections. Comparative clinical studies show fenticonazole once or twice daily to be at least as effective as six different topical antimycotics (, , , , and cyclopyroxolamine) in the treatment of superficial mycoses of the skin. Intravaginal administration of fenticonazole is associated with a high rate of microbiological efficacy in patients with vaginal candidiasis, trichomoniasis, mixed and bacterial vaginosis. Intravaginal fenticonazole is at least as effective as clotrimazole and shows similar efficacy to miconazole in patients with vaginal candidiasis. Fenticonazole has a rapid onset of action and clinical efficacy is generally observed within days of commencing treatment [Veraldi et al (2008)].

Clinical efficacy No in-vivo- resp. clinical studies were submitted. PMIC (Podesta-Marty International Consultants) et al (2013) evaluated and compared at the request of Bailleul, International SA, under strictly controlled conditions, the in vitro percutaneous absorption and skin distribution of fenticonazole nitrate, incorporated at the theoretical concentration of 2%: • Fenticonazole BAILLEUL cream • LOMEXIN® cream available on the market and considered as the reference formulation. after a single application on healthy human skin.

Percutaneous absorption through human skin was measured in vitro, using Franz™ modified diffusion cell (static type) with an effective diffusion area of 2.02 cm2.

The diffusion was monitored up to 24 hours. At the end of this exposure time, fenticonazole nitrate was assayed in the washing liquids and in the different skin structures: stratum corneum (horny layer [strips]), viable Epidermis, Dermis and in the receptor fluid (collected after: 1, 4, 8, 12, 18 and 24 hours). The mass balance of the study was calculated.

The study was performed in accordance with the standard protocol defined by the FDA & AAPS (American Association of Pharmaceutical Scientists) recommendations, the OECD 428 guidelines, the WHO report (EHC 235 for dermal absorption). The HPLC analytical method and the analysis of the samples of percutaneous absorption followed the line of conduct of the SFSTP analytical validation guide and was performed in compliance with the Standard Operating Procedures in use at PMIC.

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This in vitro technology is considered as a validated alternative test and accepted as such by the OECD (428) guideline. The following formulations were tested:

Batch / expiry date Certificate of analysis FENTICONAZOLE Nitrate (controlled and accepted) Concentration (%,m/m) FENTICONAZOLE 2% ETU0426-TRA10-05 2.01 BAILLEUL cream batch n° 29/11/2013 130715 & manufacturing date: 10/09/2013 FENTICONAZOLE Nitrate XA0354 99.04 raw material batch n° 23/04/2013 1300002486 & expiry date: 08/04/2015 LOMEXIN 2% cream Batch ETU0426-TRA08-04 1.9 n°12H27& expiry date: 29/11/2013 08/2015

This study was performed comparatively between the two formulations on skin from 6 human donors to appreciate the inter-individual variation involved.

Under the analytical conditions for this test, after a single application, it can be concluded after 24 hours of contact that: • The mass balance is fully acceptable for each formulation.

Whatever the formulation considered: • Similar amounts of fenticonazole nitrate are recovered in the horny layers (S1 and S2-S3). The first strip (S1) is classically neglected and considered as non-relevant, because it corresponds to the daily skin exfoliation. The other strips (S2-S3) are more representative of the skin surface. • Fenticonazole nitrate is recovered in the viable Epidermis in similar amounts. Whatever the above compartments analysed, there is no significant difference between the two formulations. • Fenticonazole nitrate is quantified in the dermis. High standard deviations are observed. The amounts in this compartment can be considered negligible. • Fenticonazole nitrate is quantified in the receptor fluid in only 1 cell. The amounts in this compartment can be considered negligible.

Overall, after 24 hours of contact, whatever the formulation, fenticonazole nitrate is primarily recovered in the upper layers of the skin (S2-S3+viable epidermis): • 3.938% of the dose applied for Fenticonazole BAILLEUL cream, • 3.446% of the dose applied for LOMEXIN® cream.

Total amounts of FENTICONAZOLE Nitrate (μg/cm²: mean ± standard deviation and % of dose) detected in Epidermis compartments [PMIC (2013)]

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Statistical comparison of the two formulations after 24 hours of diffusion: Statistical analysis indicating the “p” value and the corresponding statistical signification: HS: high significant, S = significant for p ≤ 0.05, NS = non-significant [PMIC (2013)].

The aim of this study was, after a single application on healthy skin, to evaluate and compare under strictly controlled condition, the in vitro percutaneous absorption and skin distribution of fenticonazole nitrate, incorporated at the theoretical concentration of 2% in Fenticonazole Bailleul cream, Lomexin cream as the reference formulation. The amounts are regarded as equivalent and to demonstrate that the penetration is limited to the external structures of the skin when the formulation is applied on healthy human skin.

In the experimental conditions of the study, according to time and regarding the formulations applied, it appears that Fenticonazole BAILLEUL cream presents a distribution profile identical to the one of currently registered LOMEXIN®. It was concluded that these two formulations have the same behaviour after a single topical application on human skin during a 24 hour contact, they were regarded as similar [PMIC et al (2013)].

The applicant submitted a compilation of clinical trials of fenticonazole containing topical products in the treatment of dermatological infections.

Clinical safety No clinical safety studies were conducted (see above). Safety data were compiled by recent literature. In a tolerability study, fenticonazole 2% cream was applied to the back of ten volunteers (2% cream) once a day for five consecutive days. No fenticonazole was detected in the plasma tested on the last day of the investigation; the sensitivity limit of the analytical method used was 50 ng/ml [Data on file Recordati S.p.A. in Fioroni et al (1990)]. The negligible amounts of drug absorbed are highly unlikely to cause any systemic adverse reactions, as already indicated by the mass of evidence from clinical and postmarketing surveillance studies [Fiorini et al (1990)].

Local tolerance: Fenticonazole 2% cream, lotion/solution, foam and powder were well tolerated when administered for up to 4 weeks in patients with cutaneous mycoses, pityriasis versicolor, dermatomycoses or tinea pedis. The most common adverse events associated with topical application of fenticonazole were burning sensation/cutaneous irritation and itch on application, which occurred in 1.1-6.0% [Leiste et al (1989), Odeh et al (1990), Rabbiosi et al (1989) in Veraldi et al (2008)] and 1.1-10.0% [Altmeyer et al (1990b), Odeh et al (1990), Vannini et al (1988) in Veraldi et al (2008)] of patients, respectively. However, in a large number of studies, no adverse events were reported [Altmeyer et al (1990a), Clerico et al (1987), Finzi et al (1986), Jung et al (1988), Kokoschka et al (1986), Stetter (1984), Persi et al (1985), Fioroni et al (1990) in Veraldi et al (2008)]. In a large (n = 760), open-label study, adverse events were reported in 3.8% of fenticonazole recipients and these precipitated drug discontinuation in approximately 1% of patients [Sartani et al (1988) in Veraldi et al (2008)]. Other adverse events occurring in >1% of patients following topical application of fenticonazole included

Fenticonazol Bailleul 20 mg/g Crème, DE/H/5048/001/DC Public AR 8/10 erythema [Odeh et al (1990), Vannini et al (1988) in Veraldi et al (2008)] and desquamation [Aste et al (1988), Aste et al (1987) in Veraldi et al (2008)].

Pigatto et al (1990) performed a double blind, randomized clinical trial on twelve healthy volunteers to evaluate the irritation potential of fenticonazole 2% cream (Lomexin®) and spray versus miconazole 2% cream and econazole 1% spray. The contact-sensitizing potential of the two fenticonazole preparations was also investigated. There was no evidence of irritation after the treatments with fenticonazole cream, its excipients, miconazole cream and fenticonazole spray excipients, whereas signs of irritation were observed in four cases after treatment with the spray formulations (two after fenticonazole, two after econazole). The contact-sensitizing test was performed only with fenticonazole 2% cream and spray. Neither spray nor cream formulation of fenticonazole showed evidence of sensitization in any of the twelve subjects [Pigatto et al (1990)].

A double-blind, randomized clinical trial was performed by Lechuga et al (1990) on twelve healthy volunteers to evaluate the irritation and contact-sensitizing potential of fenticonazole 2% cream and spray versus miconazole 2% cream and econazole 1% spray. The study period for each subject was 72 hours irritation test, 5 days wash-out and 2 weeks contact-sensitizing test. There was no evidence of irritation after treatment with fenticonazole cream, its excipients, miconazole cream and fenticonazole spray excipients, whereas signs of irritation were observed in four cases after treatment with the spray formulations (two after fenticonazole, two after econazole). Neither spray nor cream formulations of fenticonazole showed evidence of sensitization in any of the twelve subjects. No systemic adverse reactions were noted and no subject had to be withdrawn from the study [Lechuga et al (1990)].

Contraindications/warnings: Burning and itching have been reported after the application of fenticonazole nitrate [Martindale et al (2011a)]. Given the identical composition of the reference – and the product under discussion the omission of clinical studies containing a placebo and an active comparator (Lomexin) seem acceptable; otherwise clinical studies (three arm favoured) would have been necessary and consequently would have been claimed to demonstrate therapeutic equivalence. In this particular case the submitted in vitro data are not only regarded as supportive but as sufficient. Given that Batch E02 of the applied product contains some greater particles as the reference product, although particular deviations with regard to tolerability are not expected (cf quality comment as well), results of ancillary tolerance studies should be submitted. SmPC (and PIL accordingly) should be adapted to that of the reference product (with special regard to sections 4.1. and 4.4).

Legal Status The prescription status should be determined on national basis. In Germany: Pharmacy only.

User Testing User testing for Fenticonazol Bailleul 20 mg/g Creme has not been conducted. This was justified by the similarities between the PL of Candifen 600 mg vaginal soft capsules (DE/H/5048/002/DC, which was assessed to be sufficiently user tested) and the corresponding cream, so that the necessary guidance for bridging was met. However, during the authorization procedure the application for the vaginal capsules was withdrawn based on company’s marketing strategy. The applicant´s argumentation is plausible, the PL of Fenticonazol Bailleul 20 mg/g Creme is compliant with the respective Guideline on the readability of the labelling and package leaflet of medicinal products for human use, Revision 1, 12 January 2009.

Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

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Risk Management Plan The Applicant has submitted a RMP describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the following medicinal product: Fenticonazol Bailleul 20 mg/g Creme.

The following summary of the safety concerns is included in the proposed RMP: Important identified risks  Hypersensitivity reactions Missing information  Exposure during lactation  Exposure during pregnancy  Exposure in infants and children younger than 12 years

Proposed pharmacovigilance activities: - Routine pharmacovigilance.

Proposed risk minimisation measures: - Routine risk minimisation.

The proposed summary of the safety concerns is deemed acceptable. The proposed routine pharmacovigilance activities and routine risk minimisation measures are considered sufficient. The applicant confirmed that the date of final sign off will be replaced by date of signature and the RMP will be signed and submitted with the closing sequence. The revised RMP is therefore acceptable.

Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. • For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV. BENEFIT RISK ASSESSMENT From the quality, non-clinical and clinical-dermatological point of view the benefit risk ratio is positive and the application is approved. For intermediate amendments see current product information.

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