Decentralised Procedure Public Assessment Report Biofanal Kombi

Decentralised Procedure

Public Assessment Report

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten

Nystatin

DE/H/5526/001/DC

Applicant: Dr. Pfleger Arzneimittel GmbH

Date: 7th September 2020

This module reflects the scientific discussion for the approval of “Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten”. The procedure was finalised on 14.11.2019.

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 ...... 5 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 ...... 6 III.3 Clinical aspects ...... 6 IV. BENEFIT RISK ASSESSMENT ...... 10

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 2/10

ADMINISTRATIVE INFORMATION

Name of the medicinal product in the Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. RMS Vaginaltabletten

Name of the drug substance (INN name): Nystatin

Pharmaco-therapeutic group G01AA01 (ATC Code): Ointment + vaginal tablet; Pharmaceutical form(s) and strength(s): 100 000 I.U./g and 100 000 I.U. per vaginal tablet

Reference Number(s) for the Decentralised Procedure DE/H/5526/001/DC

Reference Member State: DE BE, DK, FI, LU, NL, NO, SE Concerned Member States: Withdrawal NL during clock stop

Legal basis of application: Bibliographic Art 10 a Dir 2001/83/EC Dr. Pfleger Arzneimittel GmbH Dr.-Robert-Pfleger-Str. 12 Applicant (name and address) D-96052 Bamberg Germany

Dr. Pfleger Arzneimittel GmbH Names and addresses of all proposed Dr.-Robert-Pfleger-Str. 12 manufacturer(s) responsible for D-96052 Bamberg batch release in the EEA Germany

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 3/10

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten, indicated for the treatment of vulvovaginal candidiasis in adults, is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement This is a bibliographic application according to Art. 10 a Dir 2001/83/EC for nystatin vaginal tablets and ointment as combi-pack.

II.2 About the product The applicant applies for nystatin vaginal tablets and ointment as combi-pack (one tube containing 25 g of nystatin 100,000 IU ointment and one blister containing six nystatin 100,000 IU vaginal tablets), under trade name Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten. Biofanal® 100,000 IU Combi-Pack has been already approved in DE since 1989 (re-registration in 2004) for the local treatment of infections of the vagina and outer areas of the genitals caused by proven nystatin-sensitive yeasts. Each of the two components contained in the Biofanal® 100,000 IU Combi- Pack has been approved and distributed in DE as a single product without any changes regarding its quantitative and qualitative composition since their market launch in 1978.

The indication applied for is as follows: Biofanal Kombi is indicated for the treatment of vulvovaginal candidiasis in adults (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antimycotic agents.

Posology and method of administration according to submitted SmPC: Ointment Posology Twice daily to the infected skin areas on the outer areas of the genitals.

Method of administration and duration of treatment For cutaneous use. The ointment should be applied not too thinly twice daily to the infected skin areas on the outer areas of the genitals (at the beginning of treatment once a day concomitantly with application of the vaginal tablet). The ointment should be used until complete recovery. The necessary duration of treatment for this is usually on average 2 to 4 weeks. If necessary, the ointment can be used for longer. Clinical studies regarding tolerance are available regarding use for up to 2 weeks.

Vaginal tablets Posology One or two vaginal tablets once daily.

Method of administration and duration of treatment For vaginal use. Short term treatment: Two vaginal tablets should be inserted deeply into the vagina on three consecutive days before going to bed concomitantly with the ointment. 6 day treatment: One vaginal tablet should be inserted deeply into the vagina on six consecutive days before going to bed concomitantly with the ointment.

A subsequent medical examination should clarify whether the treatment has been successful or should be continued. If the latter is the case, then the treatment can be extended until complete cure.

Paediatric population The safety and efficacy of Biofanal Kombi in children and adolescents has not been established. No data are available.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 4/10

II.3 General comments on the submitted dossier This is a bibliographic application according to Art. 10 a Dir. 2001/83/EC. Nystatin is a well- known antifungal substance. It has been used for cutaneous, mucocutaneous and vaginal mycotic infections since about 50 years. The combined therapy of vulvovaginal candidiasis with nystatin vaginal tablets and nystatin external ointment has been well established since many years and is in line with current treatment guideline recommendations. Therefore, the well-established use application is acceptable. It should be considered that Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten has been already approved in DE since 1989 (re-registration in 2004) for the local treatment of infections of the vagina and outer areas of the genitals caused by proven nystatin-sensitive yeasts. Each of the two components contained in the submitted Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten has been approved and distributed in DE as a single product without any changes regarding its quantitative and qualitative composition since their market launch in 1978. Therefore, the Applicant submitted clinical data related to the product under application in addition to literature data. Since the submitted clinical data support the relevance of the literature, this approach can be regarded as acceptable.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles GMP The RMS has been assured that acceptable standards of GMP are in place for these product types at the site Dr. Pfleger Arzneimittel GmbH, Germany, which is responsible for the manufacture, packaging, batch control and batch release of the drug products of the current DCP procedure. For this manufacturing site within the Community, the RMS has accepted copies of the current manufacturer authorisation and the GMP certificate issued by the inspection service of the competent authority as certification that acceptable standards of GMP are in place at this site. The competent authority has additionally confirmed that vaginal tablets are covered by the current manufacturing authorisation. Additionally, a copy of the GMP certificate of the competent Italian authority for the active substance manufacturing site has been provided for the manufacture of nystatin, based on an audit not older than 3 years. There is no manufacturing site of the drug product outside the Community. The QP declaration for nystatin is based on an audit not older than 3 years and is accepted.

GCP N/A

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The active substance is nystatin. The active substance is covered by a Ph. Eur. monograph. The CEP procedure is used. A copy of the valid CEP is provided in module 1. The applicant´s drug substance specification is acceptable. According to the CEP the re-test period of the drug substance is 3 years if stored in double polyethylene bags in a sealed aluminium laminate bag in a carton box.

Drug Product The DC procedure concerns a combination package of vaginal tablets, containing 100000 IU nystatin/tablet and an ointment, containing 100000 IU nystatin/g. The qualitative and quantitative composition as well as the drug product manufacturer corresponds to the nationally approved vaginal tablet and ointment, including combination package, marketed under the name Biofanal. All excipients are well-known. Pharmaceutical development is described. The manufacturing process is described, and validation results are presented. The excipients of the vaginal tablet are specified according to Ph. Eur. The excipient of the ointment is non-pharmacopoeial and is specified according to DAC (Deutscher Arzneimittel Codex). The release and shelf-life specification of the drug products are provided and cover relevant parameters. The analytical procedures are described and validated. Compliant batch results are presented.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 5/10

The vaginal tablet is packaged in a blister. The ointment is packaged in an aluminium tube with an inner epoxy-phenol lacquer. The container closure systems are adequately described and specified. A shelf-life of 3 years at not more than 25°C is proposed for the vaginal tablet and the ointment, and an in-use shelf-life of 4 weeks is proposed for the ointment. For the vaginal tablets, the storage recommendation “Store in original package in order to protect from light” is additionally applied. The shelf-life of both dosage forms, the in-use shelf-life of the ointment and the storage instructions are justified by the stability data.

III.2 Non-clinical aspects There are no objections to approval of Nystatin 100 000 I.U. combi-pack from a non-clinical point of view provided that the issues on ERA will be solved satisfactorily.

Environmental Risk Assessment (ERA) The applicant submitted a letter of commitment to provide a complete and adequate updated ERA according to the EMA guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2*, June 2006) for Nystatin after completion of Phase II studies in a stepwise manner as post-marketing measure (PAM).

A final conclusion on potential risk of Nystatin to the environment cannot be drawn based on the available data yet. Updated ERAs will be presented after completion of the OECD 201, OECD 211, OECD 301, and OECD 209 studies at the end of 2020 and of OECD 106 and OECD 308 studies in 2023 as PAM.

III.3 Clinical aspects Pharmacokinetics Literature data indicate that nystatin is barely or not absorbed through skin or mucous membranes. This is in line with information given in PI of nystatin containing products intended for vaginal and external use. In addition, the medicinal product under application Biofanal® 100,000 IU Combi-Pack has been already on the market in DE since many years. There is no need for further investigations regarding pharmacokinetics.

Pharmacodynamics Nystatin is a polyene antifungal antibiotic produced by the growth of the bacteria Streptomyces nursei, Streptomyces aureus, and other Streptomyces species. Nystatin interferes with the permeability of the cell membrane of sensitive fungi by interacting with the membrane sterols, chiefly ergosterol. Sterols play a vital role in membranes, and this function is seriously disturbed once polyenes bind to and/or sequester them. Essential membrane proteins of fungi obviously require sterols for their activity, stability and/or regulation. Among the various membrane protein/ergosterol interactions, which are discussed as targets for polyene antimycotic reaction, the focus is on transport proteins of the fungal plasma membrane. The fatal complementary effects of alterations in the cell membrane are subsequent leakage of vital intracellular constituents, destruction of the proton gradient and ultimately the potential death of the organisms.

Nystatin is an antibiotic, which is both fungistatic and fungicidal in vitro against a wide variety of pathogenic and nonpathogenic yeasts and fungi including the major pathogenic fungi such as Candida and Aspergillus species.

Candida albicans is the main pathogen of vulvovaginal candidiasis, followed by non-albicans Candida species, especially C. glabrata, in the remaining cases.

In addition to literature data, the Applicant provided results of two in vitro studies (P232 performed in 2006; P327 performed in 2015), which investigated susceptibility of important fungal pathogens to nystatin. Overall, the data support susceptibility against relevant fungal pathogens. Pharmacodynamics properties of nystatin have been described sufficiently.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 6/10

Clinical efficacy The consensus guideline of four professional German societies (Brasch et al. 2014, Mendling 2015) and the Clinical Practice Guideline for the Management of Candidiasis by the Infectious Diseases Society of America (Pappas et al. 2009, 2015) recommend for the treatment of uncomplicated vulvovaginal candidiasis topical antifungal agents. These drugs, belonging to the polyene (nystatin) and azole families (imidazole derivatives: butoconazole, clotrimazole, econazole, fenticonazole, miconazole, tioconazole, ternaconazole), are therapeutically used in the form of creams, ointments, vaginal tablets or vaginal suppositories. No evidence exists to show the superiority of any one formulation or regimen (Pappas et al. 2009, 2015, Mendling 2015).

Nystatin vaginal tablets 100,000 IU/200,000 IU daily are recommended to administer for 6 or 14 days (Mendling 2015, Pappas et al. 2009, Drugs.com 2016, Toxnet 2016, AHFS 2007).

Alternatively, a single 150 mg oral dose of fluconazole is recommended (Pappas et al. 2015, Sherrard et al. 2011, Mendling 2015). Oral and locally applied antifungal formulations have been shown to achieve entirely equivalent results (Pappas et al. 2015). The combination of intravaginal treatment of acute vulvovaginal candidiasis with additional cream for the vulva appears to produce better treatment results than intravaginal treatment alone (Mendling 2015).

For C. glabrata vulvovaginitis intravaginal nystatin, e.g. administered as suppositories, 100,000 IU daily for 14 days is strongly recommended in the IDSA guideline (Pappas et al. 2015).

The efficacy of Biofanal® 100,000 IU vaginal tablets in combination with Biofanal® 100,000 IU ointment was demonstrated in a prospective, controlled randomised clinical study in 118 patients with acute, culture-confirmed mycotic infection (Göttlicher 1989). The objective of this trial was to compare the clinical outcome of a 6-day therapy with 100,000 IU of nystatin per vaginal tablet (Biofanal® vaginal tablets) once daily (n = 50 patients, mean age 31.5 years) with that of 3-day therapy with 200,000 IU of nystatin per vaginal tablet once daily (n =54 patients, mean age 26.5 years), and additionally, a 3-day therapy with 100,000 IU of nystatin per vaginal tablet once daily (n =46 patients, mean age 31.3 years). All patients received supplementary treatment with nystatin ointment (Biofanal® ointment) for locally use and, if they had a sexual partner, for partner treatment. In the 600,000 IU dose groups, the success rate of 6-day treatment (88%) was nearly equal to that of 3-day treatment (83.3%), as ascertained by culture. Three-day treatment with the lower total dose (300,000 IU of nystatin) performed significantly worse, with a success rate of only 67.4%. In all three groups, there were no significant differences between the subjective success degree of treatment as perceived by the patients and the objective treatment outcomes determined by the investigators based on clinical tests measuring the extent of fungal infection after treatment as a measure of treatment success. The author concluded that a 3-day regimen with 200,000 IU nystatin per vaginal tablet once daily is nearly equivalent to the conventional 6-day regimen with 100,000 IU nystatin per vaginal tablet once daily in terms of treatment success and is thus an acceptable compromise in view of a probably improved patient’s compliance. The outcome of this investigation has been confirmed by the results of two non-interventional studies, which were conducted by the applicant to obtain more information about how a treatment with Biofanal® Combi-Pack will perform in routine clinical practice (AWB-049, AWB-053). The results of these studies are in accordance with previous investigations published in the literature, in which a locally acting nystatin formulation was applied as vaginal tablets or pessaries. Mycological cure rates ranging between 64% and 96%, depending on the different regimens of antifungal therapy, were reported (Pigott 1972, Milne & Brown 1973, Velupillai & Thin 1977, Konnegen et al. 1980). Overall, the combined therapy of vulvovaginal candidosis with nystatin vaginal tablets and nystatin external ointment in the applied dosage has been well established since many years and is in line with current treatment guideline recommendations.

Clinical safety It is generally accepted that nystatin, when applied locally, is well tolerated, even during prolonged use.

Biofanal® Combi-Pack has been available in DE in an unchanged form since 1989. In addition, each of the two components contained in Biofanal® Combi-Pack, vaginal tablets (Component 2) and

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 7/10 ointment (Component 1), has been distributed in DE as a single product (Biofanal® vaginal tablets; Biofanal® ointment) without any changes in its qualitative and quantitative composition for many decades. Therefore, the safety profile of each product under every-day life conditions is very well defined.

Between 2007 and September 2016, 1,668,930 packages of Biofanal® vaginal tablets (including Biofanal® Combi-Pack) and 1,629,225 packages of Biofanal® ointment (including Biofanal® Combi- Pack) were distributed to the market. The applicant has documented all adverse drug reactions (ADRs) that may or may not have been associated with exposure to Biofanal® vaginal tablets and/or Biofanal® ointment (including Biofanal Combi-Pack) in an intern Access Data Base from 01.01.1995 to 31.12.2006 and from 01.01.2007 to the present day in the ongoing Pharmacovigilance Data Base Saphaeus. All spontaneous serious and nonserious reactions from clinical studies and from marketing experience, and ADRs from non-interventional studies and other non-interventional solicited sources were considered. Overall, a total of 40 ADRs were reported by 26 patients during the recording period. Of these, 17 ADRs were assessed as possible/probable/likely (itching, redness, burning, skin erosion, acute generalised exanthematous pustulosis, contact dermatitis) related and 3 as certain related (reddening, maceration, itching). No potential risks, which have not been included in the current approved SmPCs of nystatin containing drug formulations of the applicant could be identified.

In addition to the acquisition of these data, the applicant wanted to gather information to local tolerability after the combined treatment with his nystatin containing vaginal tablets and nystatin containing ointment (Biofanal® Combi-Pack) and chose to perform a patient-blinded clinical study in healthy female volunteers (P200, performed in 2002). Twenty women received two multiple dose regimens, one treatment with nystatin and one treatment with placebo, in a randomised fashion during the study, with a wash-out phase of ten days. On 12 consecutive days, women applied either two nystatin vaginal tablets once a day in the evening (Biofanal® vaginal tablets) and simultaneously nystatin ointment (Biofanal® ointment, 0.5-1g ointment once on day 1 (evening) and b.i.d. (morning and evening) on days 2-12, i.e. 23 x 50,000-100,000 IU of nystatin) or the placebo treatment applied in the same manner. The frequency of AEs was very low throughout the study and no serious AEs occurred. There was no clinically relevant difference between the active and the placebo treatment. Only one adverse event with placebo treatment (application site reaction) was considered to be possibly drug related.

The aim of a second open label controlled study phase II performed in 1998 by the applicant (P147) was to evaluate the local tolerability of his nystatin ointment formulation (Biofanal® ointment) in different skin types (normal, sensitive and atopic). Overall, no skin reactions were detected at the application site of either Biofanal® ointment or placebo during the first 72 hours after application in any of the 50 subjects tested. No adverse reactions were reported. In line with literature data as well as study data related to the product under evaluation it can be concluded that nystatin, when applied locally, is well tolerated. The safety profile as outlined in the submitted SmPC was defined based on results of clinical studies and long-term post marketing experience of this product, which is already marketed since many years in DE.

Legal Status The medicinal product is not subject to medical prescription.

User Testing The User Testing as provided by the applicant is acceptable.

Summary Pharmacovigilance system The applicant has submitted a signed Summary of the applicant's and/or 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.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 8/10

Risk Management Plan The applicant 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 the medicinal product(s) applied for authorisation.

Safety specification

Summary of safety concerns Important identified risks • None Important potential risks • None Missing information • None

Pharmacovigilance Plan Summary Table of additional Pharmacovigilance activities Not applicable

The applicant proposed only routine pharmacovigilance activities, which is endorsed by the RMS.

Risk minimisation measures Summary of risk minimisation measures Not applicable

The applicant proposed only routine risk minimisation measures, which is endorsed by the RMS.

Summary of the RMP Overall, the submitted Risk Management Plan is considered acceptable. The Applicant is informed that few minor issues according to GVP Module V (Rev. 2) and the “Guidance on format of the risk management plan (RMP) in the EU” are still present. The RMS recommends, that these issues should be considered within the next upcoming regular update of the RMP.

An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. - If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

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. • In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 9/10

IV. BENEFIT RISK ASSESSMENT The application for marketing authorization is approvable from the quality, non-clinical and clinical point of view. The application is approved. For intermediate amendments see current product information.

Biofanal Kombi 100000 I.E./g Salbe und 100000 I.E. Vaginaltabletten , DE/H/5526/001/DC Public AR 10/10