Decentralised Procedure Public Assessment Report Fluomizin 10

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Decentralised Procedure

Public Assessment Report

Fluomizin 10 mg Vaginaltabletten

Dequalinium

DE/H/2422/001/DC

Applicant: FGK Representative Service GmbH

Reference Member State: DE

TABLE OF CONTENTS

I. INTRODUCTION...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 Problem statement ...... 4 II.2 About the product ...... 5 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 ...... 9 IV. BENEFIT RISK ASSESSMENT ...... 22

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 2/22

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Fluomizin 10 mg Vaginaltabletten product(s) in the RMS INN (or common name) of the active Dequalinium substance(s): Pharmaco-therapeutic group G01AC05 (ATC Code): Pharmaceutical form(s) and Vaginal tablet strength(s): Reference Number(s) for the DCP DE/H/2422/01/DC

Concerned Member States: AT, BE, CZ, ES, IT, LU, PL, PT and SK Withdrawn: HU

Applicant (name and address) FGK Representative Service GmbH Heimeranstr. 35 80339 Muenchen Germany

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 3/22

I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Fluomizin 10 mg vaginal tablets, indicated for the treatment of Bacterial vaginosis, is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement The sought indication BV is the most common cause of vaginal infections in women of reproductive age. It is a complex, polymicrobial, ecological disease of the vaginal flora characterized by a disturbance in normal vaginal flora and a shift in the vaginal microenvironment. There is a reduction in the amount of normal commensal hydrogen peroxide- and acid-producing lactobacilli and an overcolonization with other bacterial species including Gardnerella vaginalis, obligatory anaerobic Gram negative rods, Mobiluncus species, Bacteroides species, Prevotella species, Peptostrepto- ccocus species and Mycoplasma hominis. However, most of these organisms also form part of the endogenous vaginal flora and are not specific for BV. Despite an increasing understanding of the pathogenesis of BV, the causative organism(s) remain unknown. Although Gardnerella vaginalis and selected anaerobic bacteria can be found in virtually all women with BV, DNA technology demonstrates the presence of a large number of unculturable or very difficult-to-culture anaerobes, and no causative role has been established for any of these microbes One theory is that destabilization of Lactobacillus species is the key in development of BV and that G. vaginalis and the anaerobes are secondary invaders. Certainly, no single bacterium is considered causative of BV.

Due to the complex microbiological nature of BV and the lack of a causative microorganism, it is not recommended to perform vaginal cultures. The standard method for diagnosing BV uses therefore clinical criteria that were developed by Amsel and co-workers. These criteria have proved to be remarkably simple and useful in clinical practice: - a vaginal pH higher than 4.5 - the presence of clue (vaginal epithelial) cells in the vaginal fluid - a thin, grey or white homogenous discharge - a positive KOH test (the release of an amine (fishy) odour upon the addition of 10% potassium hydroxide to the vaginal fluid

Typically, bacterial vaginosis is diagnosed if 3 of the 4 Amsel criteria are present. The presence of clue cells is the single most reliable indicator of BV. The four Amsel criteria are regarded as the accepted standard for diagnosis and clinical cure of BV.

It is unclear whether or not BV is a sexually transmitted infection. It is often associated with sexually transmitted disease risk factors, such as multiple sexual partners, but obtaining proof of sexual transmission is impossible because no single sexually transmitted pathogen has been isolated. However, evidence for sexual transmission in the pathogenesis of BV, although controversial, continues to accumulate. Although treatment trials of heterosexual partners using imidazoles and clindamycin have not shown a benefit in preventing recurrence, cross-sectional studies have shown associations with BV and high-risk practices observed with sexually transmitted infections.

Recurrent BV is common: 15 – 30% of women have symptomatic BV recurrence 30 – 90 days following therapy and up to 50 to 70 % recur within 12 months. Current knowledge indicates that independent of the type of initial treatment, the number of patients with BV recurrence increases to similar rates within 3 to 6 months post treatment. The main reasons for recurrence are sexual or personal behaviour and other factors interfering with the establishment of a normal vaginal flora, rather than initial failure to eradicate BV-associated pathogens. The reasons for BV recurrence are not yet completely understood.

BV has been shown to be an independent risk factor for more serious sequelae such as acquisition of sexually transmitted infections, acquisition and potential transmission of human immunodeficiency virus (HIV), development of pelvic inflammatory disease (PID), premature delivery, and premature rupture of amniotic membranes.

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 4/22

Currently-available medications include antibiotics and to a lesser extent antiseptic agents. Antibiotics with activity against anaerobes, typically metronidazole and clindamycin applied vaginally or taken orally, are the mainstays of therapy. These antibiotics have differing spectra of activity but equivalent short-term efficacy, with cure rates of 70 – 90 % at 1 month. The proportion of women in whom BV relapses also increases over time and seems to be independent of whether metronidazole or clindamycin was used for the initial therapy. As an alternative to antibiotics, antiseptic agents, such as dequalinium chloride, povidone iodine, chlorhexidine HCl, hexetidine, have been used to treat BV. These less specific agents have a broad spectrum of antimicrobial activity and resistance of pathogens is unlikely due to the mode of action of antiseptics. In view of the possible occurrence of resistance associated with antibiotics, there is a need for additional therapeutic options for the treatment of BV.

II.2 About the product The drug product is presented as a vaginal tablet containing 10 mg of the drug substance dequalinium chloride. Dequalinium chloride exhibits a broad antimicrobial spectrum against gram-positive and gram- negative bacteria, yeasts, and protozoa. It is a well-known anti-infective and antiseptic agent used for topical application in the treatment of vaginal, dermal, buccal and pharyngeal infections.

II.3 General comments on the submitted dossier This decentralised procedure is an Article 8(3) application with the known active substance dequalinium chloride and seeks for the indication “Bacterial vaginosis (BV)”. The posology is one vaginal tablet daily for six days.

The product has been marketed in Germany as Fluomycin N in the same composition since 1993 for the treatment of vaginal infections of bacterial and mycotic origin, against trichomoniasis and to achieve asepsis prior to gynaecological surgery and births. It has been approved in Switzerland as Fluomizin in the same composition since 2002 (MA no 55 919) for the treatment of fluor vaginalis of bacterial and mycotic aetiology (e.g. bacterial vaginosis and candidiasis).

This application comprises one new pivotal controlled, randomised, single-blind study comparing against clindamycin (Study 380104), a controlled, randomised, double-blind study, in comparison with 200mg Iodine-PVP (Study FLU193) and a post-marketing drug utilisation study (Study FLU399) in various indications. In addition an extensive up-to-date literature survey is provided.

Scientific advice was sought at the BfArM at 26.01.2007.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. 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.

According to the applicant, the studies presented in this application (380104, FLU193, FLU399) were conducted in compliance with Good Clinical Practice.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance dequalinium chloride is a compendial compound. For the drug substance manufacturer, the quality of the drug substance is described via an Active Substance Master File. Letters of access and written confirmations are given.

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 5/22

The manufacturing process of the drug substance is described in detail. Potential impurities (related substances, residual solvents) arising from the manufacturing process are discussed. The quality of the drug substance is controlled by a drug substance specification which is in compliance with the Ph. Eur. monograph “dequalinium chloride”. Batch analysis data are given which demonstrate the conformance with the drug substance specification. Stability studies on three batches at long-term conditions over 60 months respectively 48 months and accelerated conditions ( two batches) over 6 months have been provided. Based on these data a re-test period of 5 years, if stored in well-closed and light resistant containers, is justified.

Drug product Fluomizin vaginal tablets are white or almost white, oval, biconvex tablets which are packed in PVC/PE/PVdC blister with an aluminium push through foil. Each tablet contains 10.00 mg dequalinium chloride, Ph. Eur. as active substance. All excipients used are compendial.

The pharmaceutical development of the drug product is adequately described.

The drug product is manufactured, batch released, and packaged by Rottendorf Pharma GmbH, Germany. As alternative manufacturer for packaging, Ivers-Lee Ltd., Switzerland is stated. For batch release and importation Haupt Pharma Amareg GmbH, Germany is responsible. For each of the manufacturers, satisfactorily manufacturing authorisations are provided.

The manufacturing process including in-process controls and critical steps is adequately described. Sufficient process validation data are given which show that the manufacturing process can produce a reproducible product.

The proposed release and shelf life specifications contain all quality relevant characteristics required for this pharmaceutical form. The test procedures are described in a detailed manner and are satisfactorily validated. The acceptance criteria in the release and shelf life specifications are adequately justified. Batch analysis data showing the compliance with the current release specification are provided.

Long-term stability data for three batches over 36 months, results of intermediate studies over 36 months, and accelerated study results over 12 months are given which support a shelf life of 36 months.

III.2 Non-clinical aspects Pharmacology Dequalinium chloride, a topical anti-infective and antiseptic agent belonging to the class of quaternary ammonium compounds, exhibits a broad antimicrobial spectrum against Gram-positive and Gram-negative bacteria, fungi (yeasts), and protozoa. The clinical use of dequalinium chloride as a topical anti-infective and antiseptic is well established. Over the last four decades, a number of different formulations have been used for various indications including topical application in the treatment of vaginal, dermal, buccal and pharyngeal infections. Tablets containing 10 mg dequalinium chloride have been used in Germany for 30 years for local treatment of various vaginal infections. Its good efficacy and local tolerability has been demonstrated in a number of clinical studies. Given the history of clinical use of dequalinium chloride, there is a significant body of published and publicly available data on dequalinium chloride and other dequalinium salts. These data are supplemented by published data on other quaternary ammonium compounds of the same class that also have anti-infective and antiseptic activity. The broad antimicrobial activity of dequalinium chloride against a wide range of important vaginal pathogens, including anaerobic and aerobic Gram-positive and Gram-negative bacteria, fungi (yeasts) and protozoa (Trichomonas vaginalis), is documented in numerous literature references and has been confirmed in 13 studies conducted by Medinova Ltd. The primary pharmacodynamics studies are reviewed in the clinical D80 assessment report. In sum: across all studies, the MIC for dequalinium chloride ranged from 0.2 to ≥ 1024 µg/mL. Gram-positive bacteria and Candida albicans were more sensitive to dequalinium chloride than gram-negative bacteria, Candida glabrata, and Trichomonas vaginalis. No development of resistance

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 6/22 of microorganisms to dequalinium chloride has been reported. An in vivo anti-infective effect is generally obtained if the concentration of the active substance at the site of action is 2 to 4 times higher than the MIC for 20 minutes up to 2 hours (Adam 1989). After dissolution of a Fluomizin tablet (10 mg dequalinium chloride) in an estimated 2.5 - 5 mL of vaginal fluid, the dequalinium chloride concentration in the vaginal fluid is estimated at 2000 - 4000 µg/mL. This concentration is assumed to be effective against microorganisms with an MIC below 1000 to 2000 µg/mL. Thus, the estimated in situ concentration of dequalinium chloride is sufficient for antimicrobial activity against all vaginal pathogens tested. Like other surface-active compounds, the primary mode of action of dequalinium chloride is an increase in bacterial cell permeability and the subsequent loss of enzyme activity, finally resulting in cell death. The broad antimicrobial spectrum of dequalinium chloride is similar to that of other quaternary ammonium compounds and anti-infectives and antiseptics of other structural classes, including chlorhexidine (Denton 1991) and povidone iodine (used as a reference compound in the Medinova studies). The antimicrobial activity has been compared in vitro to different reference antimicrobial substances (povidone iodine, hexetidine, ciclopiroxolamine, clotrimazole and metronidazole) because they are widely used in the treatment of vaginal infections. The antimicrobial activity of dequalinium chloride was much higher than that of povidone iodine against all microorganisms tested. Against anaerobic bacteria and Gardnerella vaginalis, dequalinium chloride showed similar activity as metronidazole; and the antimicrobial activity of dequalinium chloride against Candida sp. was comparable with clotrimazole and ciclopiroxolamine. The antimicrobial activity of dequalinium chloride against Candida albicans is comparable with nystatin (Collier et al. 1959).

Dequalinium chloride also exhibits several other activities, which could potentially result in side- effects in addition to its desired effects. However, since vaginally applied dequalinium chloride is only expected to be absorbed to an extremely small degree, these features are not considered relevant to the use of dequalinium chloride as a vaginal disinfectant. This is confirmed by the established clinical use and by the clinical study that is submitted with this application.

Safety pharmacology studies or studies addressing drug interactions have not been conducted. These studies would provide limited information because the drug product is only intended for topical administration and absorption is negligible.

Pharmacokinetics Dequalinium chloride in Fluomizin vaginal tablets exerts its action locally after vaginal application and is not absorbed to any high extent, therefore, conventional pharmacokinetic studies would provide limited information. A repeat-dose local tolerance study in rabbits conducted by Medinova Ltd showed that vaginal absorption of dequalinium chloride results in very low systemic absorption that does not cause toxic effects in organs. When tablets containing dequalinium chloride were administered vaginally to rabbits daily for 28 days, there was no detectable dequalinium chloride in the blood, even after repeated administration. Considering a total blood volume of 300 mL/rabbit and the detection limit of 0.05 g/mL, these results show that the amount of dequalinium chloride in blood at any time point was less than 1.25% of the lowest dose administered (1.2 mg) and less than 0.625% of the highest dosed administered (2.4 mg). Approximately 0.2% of the dequalinium chloride administered was absorbed into tissues (mostly kidney) but no morphological changes were detected. The single daily dose (mg/kg) used in this study was 2.4- to 4.8- times higher than the proposed dose in humans and the duration of treatment was 28 days compared to the recommended 6 days in humans, which corresponds to a 11- to 22-times higher total exposure (mg/kg) in rabbits compared to the proposed vaginal dose in patients.

Although the metabolism of dequalinium chloride has not been studied in animals or humans, a 2,2’- dicarboxylic acid derivative found in urine of rats and dogs has been proposed as a possible metabolite. Excretion of non-conjugated dequalinium chloride is thought to occur via the faeces. After oral or i.v. application to rats and dogs, only traces of unchanged dequalinium salts (chloride and acetate) were excreted by the kidney. The excretion route of other quaternary ammonium compounds depends on molecular weight. Compounds with low molecular weights (<156) are excreted mainly via the kidneys, whereas compounds with higher molecular weights are excreted

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 7/22 mainly via the faeces. Therefore, the probability of dequalinium chloride being excreted via the faeces is high since it is a bis-quaternary ammonium compound with a molecular weight of 528.

Toxicology The toxicity of dequalinium chloride depends on the route of administration, with the lowest toxicity and exposure seen following oral administration. In mice, the LD50 value of dequalinium chloride after oral administration (>2000 mg/kg) is approximately 100-times higher than that for i.p. administration and 1000-times higher than that for i.v. administration. Overall, dequalinium chloride has low acute oral toxicity in all species tested, although dogs seem to be less tolerant to oral dequalinium chloride than rats and mice. None of the repeat-dose studies in the literature provided information regarding the no observed adverse effect level (NOAEL) for dequalinium chloride. However, no oral toxicity was seen in rats after administration of a 0.05% dequalinium chloride solution in drinking water for 26 weeks. Toxic effects of dequalinium chloride in mice following a single i.v. dose or i.p. administration every 2 days for 30 days include a rapid and extreme decrease in body weight, dyspnoea / pulmonary congestion, and liver and kidney damage; these effects are reversible. The weight loss may be due, in part, to inhibition of cellular ATP synthesis, which would result in depletion of storage depots (fat) and the subsequent inability to produce new depots (Gamboa-Vujicic et al. 1993). In the repeat-dose local tolerance study of vaginally administered dequalinium chloride in rabbits conducted by Medinova vaginal absorption of dequalinium chloride was very low. In this study no systemic, toxicologically relevant effects after one or two administrations of dequalinium chloride vaginal tablets (1.2 mg) per day for 4 weeks were seen. Microscopic examination of liver and kidney sections from treated animals revealed no morphological changes, although there were small amounts of detectable dequalinium chloride in kidney. Thus, the NOAEL for intravaginal dequalinium chloride in rabbits was >0.8 mg/kg/day for 28 days, which corresponds to a 22-times higher total exposure (mg/kg) compared to the proposed vaginal dose in patients.

The AMES assay showed a clear positive effect in TA 1537 with dose dependent increase exceeding the effect in the positive control. To clarify the relevance of this effect for mammalian cells the antibacterial substance was tested in a HPRT test in V79 cells and a fur spot test in mice addressing the relevant endpoint of mutations. All tests in mammalian cell in vitro and in vivo were clearly negative. Sufficient exposure at the top dose in the in vivo assay can be assumed from the tox dose range finder. It can be assumed that dequalinium chloride is a bacterial mutagen. However there was no evidence for a relevant genotoxic potential in mammalian systems. Considering also the short term use and the probably very limited (if at all) systemic exposure it is regarded to have no relevant genotoxic potential for the intended clinical use.

Medinova Ltd has not conducted any specific reproductive and development toxicity studies, which is reasonable on the basis of the negligible systemic exposure of dequalinium chloride administered intravaginally and the considerable clinical experience in pregnant patients. Four clinical studies involving 181 pregnant patients did not demonstrate any adverse effect on the pregnancy or on the foetus/neonate. Furthermore, considerable post-marketing experience indicates no malformative or feto/neonatal toxicity of Fluomizin.

The repeat-dose local tolerance study of vaginally administered dequalinium chloride in rabbits conducted by Medinova showed that dequalinium chloride is well tolerated by the vaginal epithelium, although with the possibility of slight irritation following longer periods of dosing (28 days). However, all epithelia were intact and no ulcerations were found. An additional literature study has also confirmed these findings. In the Medinova study, there was an 11- to 22-fold higher total exposure (mg/kg) in rabbits compared to the proposed vaginal dose in patients. Although a minimal to mild increased vaginal irritation index was observed after treatment of rabbits with dequalinium chloride vaginal tablets, all epithelia were intact and no ulcerations were found. Tablets containing 10 mg dequalinium chloride have been used in Germany for 30 years for local treatment of various vaginal infections, and its good efficacy and local tolerability has been demonstrated in a number of clinical studies. Fluomizin / Fluomycin N / Donaxyl in its current formulation have been marketed since 1993 and, to date, an estimated total of 5.9 million patients

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 8/22 have been exposed. The most-commonly reported spontaneous adverse event was vaginal ulceration and colpitis/ vulvovaginitis, which included three SAEs, but the majority were non-serious. Ulceration was identified as a potential safety issue; however, following reduction of the recommended dose and treatment duration, as well as changes to the SPC, the frequency of reports of this type was drastically reduced (see clinical part).

The Environmental Risk Assessment for Fluomizin® cannot be finalized before a Phase II ERA has been provided by the applicant.

In conclusion, dequalinium chloride exerts its antimicrobial action locally after vaginal administration, is not absorbed to any great extent, and shows minimal toxicity. Overall, the non- clinical data confirm the clinical experience with intravaginal administration of dequalinium chloride and support the proposed indication for use of Fluomizin in the therapeutic indication of bacterial vaginosis.

Follow-up measure: An updated ERA has to be submitted by April 2011.

III.3 Clinical aspects Pharmacokinetics After dissolution of a Fluomizin tablet (10 mg dequalinium chloride) in an estimated 2.5 to 5 mL of vaginal fluid, the dequalinium chloride concentration in the vaginal fluid is estimated to be 2000 to 4000 µg/mL.

Owing to its low bioavailability, no studies of dequalinium chloride have been performed to evaluate its pharmacokinetic properties, its potential for drug-drug interactions or its metabolism and elimination. The bioavailability of dequalinium chloride is expected to be low in humans based on evidence in animals and on extensive experience of prescribed use of dequalinium chloride. Because of this expected minimal level of absorption, if studies were to be performed, it would be necessary to use radiolabelled drug, which would not be ethically justified in this situation.

For human subjects, published information on other quaternary ammonium compounds confirms that the blood levels after oral administration (10 mg to 40 mg) are generally low (of the order of ng/ml). The relative absorption of different quarternary ammonium compounds after oral application in humans has been reported to be between 0.5 and 10%. Based on the preclinical data of dequalinium chloride it is assumed that exposure following vaginal administration is even lower.

Clinical studies, a drug utilisation study of normal clinical practice, and extensive post-marketing experience with Fluomizin provide no evidence for a systemic effect of dequalinium chloride in humans. Since 1993, an estimated number of 5.9 million patients have been treated with Fluomizin. Of the total of 82 spontaneous adverse drug reactions, 27 from clinical studies and 8 from the literature, the only possibly-systemic adverse drug reactions to have been identified and incorporated into the SPC are fever, headache, nausea and allergic reactions, which were reported very rarely. This provides very reassuring evidence that dequalinium chloride is not associated with systemic adverse effects.

As summarized in the latest PSUR (December 2008), a total of 7 potential allergic reactions have been reported (4 spontaneous and 3 from own or published clinical studies). Additionally, in Study 380104 no allergic ADR has been reported in 163 patients. Fever or increased temperature has been reported in 10 cases (9 spontaneous and 1 from clinical studies). Headache has been reported in 1 case (clinical study) and 1 case was observed in Study 380104. One case of nausea was observed in Study 380104.

In summary, the available evidence suggests that dequalinium chloride is absorbed to a negligible extent and is not associated with systemic adverse effects. It is therefore considered that pharmacokinetic and metabolic studies are not warranted for this product at this time.

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 9/22

Although no specific data about the systemic availability of dequalinium chloride after vaginal use of Fluomizin are available, the data discussed by the Applicant are considered sufficient to estimate the systemic exposure. Even after oral administration, blood levels are expected to be very low. In light of the low systemic exposure in rabbits after vaginal administration and the preclinical data, PK-studies addressing the systemic exposure in humans after vaginal administration are not considered to be necessary. In addition, the expected low levels would require administration of radiolabelled drug to the patients which is not justified.

Pharmacodynamics Literature studies have shown that the mechanism of action of dequalinium chloride is primarily based on its effects on bacterial cell permeability and on bacterial proteins. Dequalinium chloride has been shown to penetrate the cells of Escherichia coli, Staphylococcus aureus and Bacillus megaterium, leaving only a very small quantity associated with the cell wall. Thus, the compound acts in the cytoplasm as well as at the bacterial surface. The antimicrobial activity of quaternary ammonium salts, in general, and dequalinium chloride, in particular, is based on the following mechanisms:

Effects on bacterial cell permeability - Adsorption on the bacterial cell surface. - Diffusion through the cell wall. - Binding to the cytoplasmic membrane, with subsequent formation of complexes and protein precipitation. In addition, the cell membrane might be lysed (depending on the concentration), resulting in perturbed osmotic exchange.

Effects on bacterial proteins and metabolic reactions after diffusion through the cell wall - Denaturation of proteins resulting in inhibition of bacterial cell metabolism. - Bacterial energy production is disrupted through inhibition of glucose metabolism and inhibition of mitochondrial ATP synthesis via inhibition of bacterial F1-ATPase. - Termination of protein synthesis, at the level of ribosomes. Initially, enzymatic inactivation might be reversible; but becomes irreversible after a longer contact time between dequalinium chloride and the bacteria.

Effects on bacterial nucleic acids - Precipitation of cytoplasmic material, with nucleic acids being the most sensitive (Hugo and Frier 1969). - Dequalinium chloride binds DNA in vitro. - Termination of protein synthesis at the level of ribosomes.

Disruption of cell permeability and subsequent loss of enzymatic activity is regarded as the primary cause of bacterial cell death after contact with surface-active compounds. Protein denaturation and inhibition of metabolic reactions are only obtained at doses above the clinical use of quaternary ammonium compounds, and are therefore less relevant for their antimicrobial action.

The bactericidal and fungicidal effect of dequalinium chloride has been demonstrated to occur within 30 to 60 minutes.

After dissolution of a Fluomizin tablet (10 mg dequalinium chloride) in an estimated 2.5 to 5 mL of vaginal fluid, the dequalinium chloride concentration in the vaginal fluid is estimated to be 2000 to 4000 µg/mL. This concentration is 4 to 8-fold greater than the MIC of the least susceptible isolate tested in vitro (MIC=512 µg/mL). The coverage of the relevant bacterial population by dequalinium chloride is therefore considered by the Applicant to be 100%. Most bacteria considered to play a role in BV were included in the in vitro data.

According to the data provided by the Applicant, dequalinium chloride is expected to be active against most pathogens expected to play a role in BV in vitro. However, microbiological data about

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 10/22 the activity of dequalinium chloride in the vaginal environment are missing and the activity of dequalinium chloride towards Atopobium vaginae have to be addressed. (Follow Up Measure 1)

In the Day 100 comment Austria raised the issue of possible interactions with condoms and similar intravaginal devices. Regarding latex condoms, the data of the Applicant are considered sufficient to demonstrate that Fluomizin is not impairing functionality. However, no data on non-latex condoms or diaphragm were provided. The respective information in the SPC is now considered adequate.

Clinical efficacy Study 380104 is the pivotal study. Supporting data from Studies FLU193 and FLU399 are included, too.

Study ID Design Study Study Subjs by Duration Gender Diagnosis Primary Posology Objective arm M/F Incl. Endpoint Age criteria 380104 controlled, 10mg Efficacy Fluom.: 6 Female, BV, Clinical randomised, OD for and 163 weeks 16-60 Amsel cure at C1 single blind six Safety Comp.: after years criteria days 152 EOT FLU193 controlled, 10mg Efficacy Fluom.: 4 to 5 Female Vaginal Total randomised, OD for and 121 weeks infections symptom double six Safety Comp.: after score blind days 59 EOT FLU399 non-inter- 10mg Safety 446 2 to 3 Female Acute Evaluation ventional, OD for and days colpitis of open-label, six Efficacy after symptoms prospective days EOT

In Study 380104, the subjects were aged 18-55 years with a diagnosis of BV. In fact the age range of participants was 16 - 54 years in the Fluomizin group and 18 - 60 years in the clindamycin group.

Subjects with other infections, or who were taking other anti-infective agents, were excluded in order to avoid interference with efficacy evaluation. The population was therefore broadly typical of the target population within this age group, apart from these exclusions. However, the study did not include older and/or post-menopausal women or young women aged <18 years. BV occurs commonly in both these age-groups, who are considered to be appropriate patients for treatment. Older, but not younger, women were included in Study FLU193 and Study FLU399; efficacy in these age-groups is discussed in section younger and older age groups.

Pregnant women were excluded from Study 380104, although it is considered important to treat vaginal infections during pregnancy in order to avoid adverse outcomes of the infection for the foetus or neonate; this is discussed in the section on pregnant women.

Patients were randomised to receive either Fluomycin (10 mg dequalinium chloride OD for six days) or clindamycin vaginal cream (2%; 100 mg OD for seven days). The dose schedules of Fluomizin vaginal tablets (10 mg once daily for 6 days) and of clindamycin vaginal cream (100 mg clindamycin for 7 days) were consistent with the prescribing information in each case.

The purpose of this phase III study was to evaluate whether vaginal tablets containing 10 mg dequalinium chloride (Fluomizin) are comparable in clinical efficacy to clindamycin vaginal crème (2%) in patients suffering from BV. The primary objective was the assessment of clinical cure rate based on the Amsel criteria (vaginal pHG > 4.5, presence of clue cells, KOH test, as well as greyish white, malodorous discharge), where clinical cure is defined as: clue cells and 2 other criteria must be negative. Secondary objectives were to evaluate: Differences between treatments on short- and long-term follow-up; Physiological status of the vaginal ecosystem during the respective treatments; Safety profile of Fluomizin

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 11/22

The primary efficacy variable was the clinical cure rate at C1. The allowed time window for the first Control Visit (C1)was 3 – 14 days after the end of treatment and for the second Control Visit (C2) 2 – 6 weeks after the end of treatment complying with guideline CPMP/EWP/558/95. There was no difference between the groups regarding median and range and also the distribution was similar.

The clinical criteria (Amsel criteria) used to assess the outcome of treatment are widely accepted for BV. The clinical cure rate at C1 is considered to be a less appropriate primary efficacy variable compared to C2. This is mainly based on the high relapse/re-infection (recurrence) rate of BV even after successful primary treatment. Therefore, assessment of efficacy will be based on the clinical outcome at C2, thus comparing initial treatment success plus early relapse of the disease. Regarding the non-inferiority margin of 15 %, this margin might be considered acceptable in light of the overall success rates in treatment of BV which are about 80%. Finally, the lower margins of the 95 % confidence intervals observed in the study are crucial for assessment of non-inferiority.

It was necessary to use a single-blind design because the formulations of the study medications were different (Fluomizin vaginal tablet and Clindamycin vaginal cream). Therefore, the procedure involved two physicians with different, clearly-defined roles.

The ‘treating’ physician issued the blinded study medication to the patient, collected partial used/unused study medication, and recorded concomitant medication, adverse events, and treatment compliance. The ‘treating’ physician was not allowed to communicate the treatment allocation to the ‘evaluating’ physician. He/she had to instruct the patient that she was not allowed to speak with the ‘evaluating’ physician about her study medication or about any complications with the study medication during treatment.

Although all patients were aware of which study medication they were using, the ‘evaluating’ physician was blinded to treatment, and was responsible for the clinical and microbiological investigational part of the clinical assessment.

The single blind design of the study is crucial and the measures taken to avoid crosstalk from the treating to the evaluating physician were explained in more detail in response to the Day 70 PAR. In the view of the RMS, a double dummy design indeed would have been the best solution from a “blinding” perspective. However, the topical use of Fluomizin and the comparator did not allow for simultaneous application of Fluomicin plus a vaginal cream placebo or Clindamycin vaginal cream plus a Fluomicin-like placebo. Especially the use of Fluomicin plus a vaginal cream placebo would have been a big problem due to the unknown (physical, chemical and biological) interactions. Different times of application would have raised other questions such as optimal time for treatment as “before bedtime” is recommended. In the opinion of the RMS comparison between an oral formulation and a new topical medicinal product would not have been a good solution as the comparability of both treatments is seriously questioned. On the basis of these considerations the RMS accepted the study design and the measures taken by the Applicant to avoid cross-talking are considered to reduce the risk of violation of the study protocol. This issue is not completely solvable from the RMS point of view but is finally considered to be acceptable. This is supported by the limited data of the double blind study FLU 193.

The study 380104 used a 2-stage adaptive design according to Bauer and Köhne (1994) using separate test statistics calculated from the disjoint samples of the study stages. This design was chosen to allow for reviewing and possibly adapting the assumption for the sample size calculation. The procedure of Bauer and Köhne for adaption of a single aspect of the study design is not compromising the overall significance level, and combines the separate p-values arising from tests before and after the pre-planned adaption of the design into a single global test statistic, controlling the overall significance level alphas. Additionally a stopping rule was defined, including early stopping when insufficient effect has been observed. Farrington and Manning reviewed several methods for the analysis of non-zero differences between treatment groups in binomial trials in the area of superiority as well as of equivalence trials. They

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 12/22 recommended the restricted maximum likelihood estimation, which was considered for the analysis of the efficacy endpoints of cure rates and improvement rates in this study, including the primary endpoints variable clinical cure rate at the first control visit. Three analysis sets were defined: - Safety analysis set (SAF): all study patients who received at least one dose of study drug. - Full analysis set/intention-to-treat (ITT): all patients, who were randomized; - Per-protocol analysis set (PPS): all patients who received at least one dose of study medication and who did not violate any major protocol criteria; The PPS population was used for the analysis of the clinical cure rate obtained from Visit C1 (primary parameter) and C2 only. The secondary parameters, and all other parameters, excluding safety, were analyzed based on the ITT population. Safety analysis was based on the SAF set. The primary analysis was based on the PPS population. According to the adaptive design, Stage 1 included all patient enrolled until interims analysis and Stage 2 included all patient enrolled after interims analysis.

Results: Due to the adaptive design, the statistical analyses were performed in two stages. Stage 1 included all patients enrolled before interims analysis, and Stage 2 includes all patients enrolled after interims analysis.

In the Fluomizin group, 28 patients were excluded from the PPS population due to 32 major protocol violations, whereas 36 patients were excluded in the clindamycin group due to 42 major protocol violations. Of these major protocol violations, the most common were time window violations (n = 12 in both groups), prior termination (Fluomizin: n = 5; clindamycin: n = 9), the investigator acted as “treating” and “evaluating” physician for the same patient (Fluomizin: n = 9; clindamycin: n = 7) and violations of inclusion or exclusion criteria (Fluomizin: n = 4; clindamycin: n = 6). There were no apparent differences in major protocol violations observed between the groups.

Demographic and baseline characteristics (including height, weight, body mass index [BMI], age and ethnic origin) of patients were comparable between both treatment groups. The study groups included patients with comparable median age and ethnic origin. The median age was approximately 30 years and all but one patient were Caucasians. The number of previous pregnancies and births in the 2 treatment groups were comparable. Approximately half of the patients had never been pregnant. The remaining patients had had at least one pregnancy.

The proportion of patients with one or more preceding bacterial vaginosis was similar among women in the Fluomizin group (69.3%) and the clindamycin group (71.7%). Approximately 24% and 34% of patients in each treatment group had experienced no or one vaginal infection, respectively. Significant previous or existing concomitant diseases were reported for 48 (29.4%) patients in the Fluomizin group and 55 (36.2%) patients in the clindamycin group.

There were no apparent treatment group differences with respect to prior or concomitant medication. Prior medication was recorded for 236/316 patients (74.7%). Oral contraceptives were the most frequently reported previous medication and the use of these was usually ongoing during the study. There were no apparent differences between the 2 groups with respect to systolic and diastolic blood pressure, heart rate or body temperature. Clinical cure rate at Visit C1 (Stage 1): Results for the primary analysis (PPS) are shown by the applicant. Clinical cure at visit C1 (PPS population) was comparable between treatment groups with cure rates of 78.8% of patients treated with Fluomizin and 76.7% treated with clindamycin. The ITT analysis of the cure rates at C1 gave similar results; there were 78.6% of cured patients with Fluomizin and 77.1% with clindamycin

Final analysis (Stage 1 and 2 combined): The results at both Stage 1 and Stage 2 (PPS) are shown in the table below, with the results of the confirmatory analysis. At Stage 2, clinical cure rates at Visit C1 were slightly higher in Fluomizin- treated patients (83.7%) than clindamycin-treated patients (81.0%).

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 13/22

Clinical cure rate at Visit C1 – Final confirmatory analysis (PPS) N N N Proportion Difference Fluomizin - clindamycin missing Cured cureda Obs. 95% CI p-value b Diff. Stage 1 Fluomizin 52 - 41 0.788 Clindamycin 44 1 33 0.767 0.021 -0.1454, 0.1875 0.02202 Stage 2 Fluomizin 86 - 72 0.837 Clindamycin 79 - 64 0.810 0.027 -0.0919, 0.1461 0.00177

Confirmatory analysis p1 (0.02202) * p2 (0.00177) = 0.00004 a Missing patients were not included in the analysis. b1-sided, Maximum likelihood estimation. CI = confidence interval, Diff. = difference, N = number of patients, obs. = observed, PPS = per-protocol set. Data source: Table 3.1A, Appendix 16.2.3.

To compare the observed overall clinical cure rates at Visit C1, the analysis of the pooled data of Stage 1 and Stage 2 are relevant. The lower limit of the 95% confidence interval for the difference between Fluomizin and clindamycin was -0.0693 in the PPS and -0.0821 in the ITT analysis, and substantially below the pre-specified non-inferiority margin of -0.15.

Based on pooled data, the cure rates for the entire PPS and ITT population for Fluomizin were 81.5% and 79.7%, respectively, and for clindamycin 78.4% and 78.7%, respectively.

Post-hoc analysis regarding BV recurrence and treatment failures were performed. The rationale for doing this is: C2 is the more relevant time point for test of cure, and thus the criteria for C1 and C2 should be the same. In the per-protocol definition there was no stringent definition for cure at C2. Post-hoc analysis of BV recurrence gave recurrence rates of 13.5% in the Fluomizin and 9.2% in the clindamycin group. The post-hoc analysis of recurrence included not only patients with recurrent disease at C2, but also patients who deteriorated and had beginning recurrence, and thus was considered clinically more relevant. The results for recurrence are shown with those for Total failure rate.

Total failure rate: Total failure rate was the total number patients who experienced BV recurrence, treatment failure and other failures, and was considered to be a more relevant clinical parameter to judge treatment effects than looking at BV recurrence rate only.

If cure status is considered at C1, no weaker criteria should be applied at C2. The Total failure rate ‘post hoc’ is the most stringent possible and thus is considered clinically more relevant.

Definition of BV recurrence and treatment failure Definition Status Including BV recurrence C1:cured; C2: not improved per protocol Total failure C1: cure status rate “per Treatment failures C2: improvement status C1: not cured; C2: not improved protocol” “per protocol” Other failures Bacterial vaginitis as AE BV recurrence C1:cured; C2: not cured post hoc Total failure C1: cure status Treatment failures rate “post hoc” C2: cure status C1: not cured; C2: not cured “post hoc” Other failures Bacterial vaginitis as AE

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Based on cure status at C1 and C2, comparable total failure rates of 23.9% and 24.3% were observed for Fluomizin and clindamycin, respectively, and failure rate was lower in the Fluomizin group (10.4%) than in the clindamycin group (15.2%). Based on cure status at C1 and improvement status at C2, similar total failure rates of 19.0% and 14.5% were observed for Fluomizin and clindamycin, respectively, and again failure rate was lower in the Fluomizin group (6.7%) than in the clindamycin group (9.2%).

Recurrence rate and Total failure rate (ITT, N = 315 Definition Number (%) of patients Fluomizin Clindamycin (N = 163) (N = 152) C1: cure status; C2: improvement status BV recurrence (C1: cured; C2: not improved) 20 (12.3) 8 (5.3) Treatment failures (C1: not cured; C2: not 11 (6.7) (7.9) 12 improved) Other failures (BV reported as AE) - - 2 (1.3) Total Failures 31 (19.0) 20 (14.5) C1: cure status; C2: cure status BV recurrence (C1: cured; C2: not cured) 22 (13.5) 14 (9.2) Treatment failures (C1: not cured; C2: not cured) 17 (10.4) 22 (14.5) Other failures (BV reported as AE) - - 1 (0.7) Total Failures 39 (23.9) 37 (24.3) ITT = intention-to-treat, N = number of patients. Data source: Table 3.2C_a, Appendix 16.2.3

Overall, the efficacy results demonstrate non-inferiority of Fluomizin compared to clindamycin. From the RMS point of view the most important data are the total failure rates in the ITT population at C2. These total failure rates summarise the primary failures at C1 and the recurrences at C2 and thus represent the final outcome at C2.

The respective data show a higher recurrence rate with Fluomizin. However, as higher efficacy at C1 outweighs this recurrence, the overall efficacy is considered very similar, i.e. non-inferiority has been demonstrated.

Regarding post-hoc analyses, the RMS requested these analyses for the reasons stated by the Applicant. Thus, basing the final assessment on these post-hoc analyses is considered acceptable, especially as the data of the post-hoc analyses are not in favour for Fluomizin compared to the primary analyses.

The supporting studies FLU193 and FLU399 support the efficacy results of study 380104 but mainly contribute to the safety database.

Clinical safety The assessment of the safety and tolerability of Fluomizin (dequalinium chloride) is based on:  two controlled clinical studies (Study 380104 in BV; Study FLU193 in vaginal infections)  a literature survey of published clinical studies with dequalinium chloride alone or in combination products (all indications)  a post-marketing drug utilisation study of normal clinical use of Fluomizin (Study FLU399)  spontaneous post-marketing adverse event reports including published reports

Of this information, only Study 380104 related specifically to treatment of BV. In all other cases, patients were treated for various vaginal infections or, in the case of published reports, also treatment

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 15/22 of non-gynaecological infections. However, it is considered appropriate to review all available safety information regarding local administration of dequalinium chloride.

In clinical studies, adverse events (AE) were recorded at clinic visits. No laboratory tests were performed but this is reasonable in view of the very low extent of absorption of dequalinium chloride with intra-vaginal administration.

Post-marketing spontaneous reports have been collected throughout the period when Fluomizin has been available and the events have been summarised and evaluated in PSURs. The effectiveness of this evaluation was demonstrated by the identification of a potential safety issue and resolution of the problem following amendment of the dosage regimen and of the SPC.

The numbers of patients treated with Fluomizin in controlled clinical studies, in the drug utilisation study, in published studies and post-marketing are summarized in Table 1.

Table 1: Overall extent of exposure

Pregnant All patients BV patients patients

Pivotal clinical study with Fluomizin 380104 163 163 Controlled clinical study with Fluomizin FLU193 121 48

Drug utilization study with Fluomizin (FLU399) 446 126 60

Published studies with Fluomizin 191 34 66

Fluomizin exposure 921 371 126 Published studies with vaginal dequalinium chloride 2049 8491) 55

Vaginal dequalinium chloride exposure 2970 1220 181

Post-marketing experience with Fluomizin 5.9 million 1) BV was clearly diagnosed for 274 patients, whereas for the remaining 575 patients the diagnosis was bacterial vaginal infection.

The exposure to Fluomizin in clinical studies is considered sufficient to draw conclusions on the safety of Fluomizin when used intravaginal. Together with the data of non-Fluomizin vaginal dequalinium chloride exposition and the post-marketing experience with Fluomizin the data pool is sufficient for a safety analysis. With respect to possible systemic exposure and resulting adverse events, data on adverse events after oral use of dequalinium chloride might further contribute to the safety assessment of dequalinium chloride.

Adverse events

Study 380104: The proportion of patients who reported at least one AE during study 380104 was lower in the Fluomizin group than in the clindamycin group (40.5% vs. 47.5%). Confirming this, the proportion of patients who reported AEs that were judged to be probably, possibly, or definitely related to study treatment was lower in the Fluomizin group (17.8%) than in the clindamycin group (20.3%).

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Overview of adverse events (SAF, N = 316) Fluomizin Clindamycin Total (N = 163) (N = 153) (N = 316) Number of AEs 134 163 297 Number of related AEsa 54 48 102 Number (%)b of patients with AEs (40.5) (47.7) (44.0) 66 73 139 Number (%)b of patients with related (17.8) (20.3) (19.0) AEsa 29 31 60 a Definitely related, probably related, or possibly related. b Percentages are based on the total number of patients per treatment group. AE = adverse event, N = number of patients, SAF = safety analysis set. Data source: Table 4.1A through 4.1D, Table 4.1F, Table 4.1G, Appendix 16.2.4.1. Listing 4.1A-C, Appendix 16.3.4.1.

The most frequently reported AEs in both Fluomizin- and clindamycin-treated patients were vaginal discharge (21.5% vs. 22.9%, respectively), vulvovaginal pruritus (11.7% vs. 18.3%, respectively), and vaginal candidiasis (8.0% vs. 7.8%, respectively).The higher frequency of AEs in clindamycin- treated patients is mainly due to the greater number of reports of vulvovaginal pruritus. Regarding system organ class, most AEs were observed in “Reproductive system and breast disorders”: 36.6% of patients treated with clincamycin had an AE in this class, whereas only 25.2% of the patients in the Fluomizin group.

Frequently reported adverse events (SAF, N = 316) System organ class Number (%)a of patients Preferred term (MedDRA) Fluomizin Clindamycin (N = 163) (N = 153) Gastrointestinal disorders 6 (3.7) 6 (3.9) Nausea 4 (2.5) 1 (0.7) Infections and infestations 27 (16.6) 24 (15.7) Vaginal candidiasis 13 (8.0) 12 (7.8) Vaginitis bacterial 10 (6.1) 7 (4.6) Nervous system disorders 3 (1.8) 6 (3.9) Headache 3 (1.8) 6 (3.9) Reproductive system and breast disorders 41 (25.2) 56 (36.6) Metrorrhagia 0 - 3 (2.0) Vaginal discharge 35 (21.5) 35 (22.9) Vulvovaginal burning sensation 9 (5.5) 11 (7.2) Vulvovaginal discomfort 0 - 3 (2.0) Vulvovaginal pruritus 19 (11.7) 28 (18.3) All AEs are listed which were reported by at least 2% of patients in any treatment group. The number of patients for system organ classes includes also those AEs which were reported by less than 2% of patients. a Percentages are based on the total number of patients per treatment group. AE = adverse event, MedDRA = Medical Dictionary for Regulatory Activities, N = number of patients. SAF = safety analysis set. Data source: Table 4.1A, Appendix 16.2.4.1.

Most of the patients with AEs had AEs that were mild or moderate in intensity. Severe AEs were reported by 8.6% in the Fluomizin group and 6.5% in the clindamycin group. The most frequently reported severe AEs in both the Fluomizin- and clindamycin-treated patients were vaginal discharge (4.3% vs. 2%, respectively), vulvovaginal pruritus (2.5% vs. 2.6%, respectively) and vulvovaginal burning sensation (1.8% vs. 2.0%, respectively) (data not shown). The “severe AEs” from this table may not be confounded with “serious AEs”; no serious were reported in this study.

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Adverse events by intensity (SAF, N = 316) Grade Number (%) of patientsa Fluomizin Clindamycin (N = 163) (N = 153) Unknown - - 2 (1.3) 1 (mild) 42 (25.8) 50 (32.7) 2 (moderate) 30 (18.4) 29 (19.0) 3 (severe) 14 (8.6) 10 (6.5) a Percentages are based on the total number of patients per treatment group. N = number of patients, SAF = safety analysis set. Data source: Table 4.1B, Appendix 16.2.4.1.

An overview of related AEs (probably, possibly, or definitely) is provided in the table below and details are presented in the next but one table. One or more related AEs (probably, possibly or definitely) were experienced by 17.8% of Fluomizin- and 20.3% of clindamycin-treated patients.

Adverse events by relationship (SAF, N = 316) Relationship Number (%) of patients a Fluomizin Clindamyci (N = 163) n (N = 153) Not related 29 (17.8) 41 (26.8) Unlikely 26 (16.0) 17 (11.1) Possibly 24 (14.7) 23 (15.0) Probably (5.2) 5 (3.1) 8 Definitely (0.7) 1 (0.6) 1 a Percentages are based on the total number of patients per treatment group. N = number of patients, SAF = safety analysis set. Data source: Table 4.1B, Appendix 16.2.4.1.

The most commonly reported related AEs in the Fluomizin group were vaginal discharge (9.2%), vulvovaginal pruritus and vaginal candidiasis (each 4.9%). The most commonly reported related AEs in clindamycin-treated patients were vulvovaginal pruritus (8.5%) and vaginal candidiasis (5.2%).

Frequently reported related AEs (SAF, N = 316) System organ class Number (%)a of patients Preferred term (MedDRA) Fluomizin Clindamycin (N = 163) (N = 153) Total number of patients with related AEs 29 17.8 31 20.3

Gastrointestinal disorders 1 0.6 1 0.7 Abdominal pain 0 0 1 0.7 Nausea 1 0.6 0 0 General disorders and administration site conditions 0 0 2 1.3 Application site bleeding 0 0 1 0.7 Pain 0 0 1 0.7 Infections and infestations 12 7.4 13 8.5 Fungal skin infection 1 0.6 0 0 Vaginal candidiasis 8 4.9 8 5.2 Vaginitis bacterial 1 0.6 6 3.9 Vulvitis 1 0.6 0 0 Vulvovaginitis 1 0.6 0 0

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Nervous system disorders 1 0.6 0 0 Headache 1 0.6 0 0 Reproductive system and breast disorders 18 11.0 20 13.1 Metrorrhagia 0 0 1 0.7 Vaginal discharge 15 9.2 7 4.6 Vaginal haemorrhage 1 0.6 0 0 Vaginal pain 1 0.6 0 0 Vulvovaginal burning sensation 3 1.8 5 3.3 Vulvovaginal discomfort 0 0 2 1.3 Vulvovaginal pruritus 8 4.9 13 8.5 Skin and subcutaneous tissue disorders 0 0 1 0.7 Eczema 0 0 1 0.7 a) All AEs are listed which were reported by at least 3% of patients in any treatment group. The number of patients for system organ classes includes also those AEs which were reported by less than 3% of patients. AE = adverse event, MedDRA = Medical Dictionary for Regulatory Activities, N = number of patients. SAF = safety analysis set. Data source: Table 4.1G, Appendix 16.2.4.1.

Study FLU193: Participants in this study had various vaginal infections including BV. Both Fluomizin and iodine- PVP were well tolerated. At the first control examination, the investigator assessed the tolerability of both study medications as ‘good’ to ‘very good’ in about 95% of the cases.

Reports of adverse events were made in 7 of 121 (5.8%) patients in the Fluomizin group. There were two reports of bleeding (one mild vaginal bleeding, one spotting) under therapy with Fluomizin, both of which resolved spontaneously after discontinuation of the treatment. No details of causality were provided in either case. One patient experienced burning, itching, redness and discharge, leading to discontinuation of the medication. This patient and another, who reported itching, were considered to have had a relapse. In addition, there were single reports of cystitis, headache, and skin rash. The investigator’s assessment of causality was possible for the headache but was not recorded for the other events.

In the iodine-PVP group, 11 of 59 patients (18.6%) reported adverse events. The most common complaint was the occurrence of burning sensation under therapy with iodine-PVP (6 reports); these were assessed as possible/probable and one patient discontinued treatment. In two cases, spotting was reported (one assessed as possible) and there were two reports of headache (possible). One report each of itching (probable) and discharge (unknown causality) were considered to be relapses.

Adverse events conclusion Most adverse events were mild, local and in favour (numerically) for Fluomizin compared to clindamycin or PVP. There is no indication that Fluomizin leads to an increased risk for adverse events in treatment of BV. Discontinuation due to adverse events is not considered a problem with Fluomizin as with the comparators.

No serious adverse events have been reported in the clinical studies. Prior to 1997, vaginal ulceration was a potential safety issue. After reduction of dose and treatment duration this serious adverse event significantly decreased. The Applicant provided data which allow estimation of frequency of vaginal ulceration with the currently proposed posology as requested in the Day 70 PAR.

Safety in special populations Pregnant and Lactating Women Gynaecological infections present a risk to the foetus and it is considered beneficial to treat the infection, taking into account the usual cautions associated with treating pregnant women.

Fluomizin in its current formulation has been marketed since 1993. The total number of patients exposed (to 31 December 2008) is estimated at 5.9 million. A marketing survey showed that Fluomizin is regularly used by physicians for the treatment of pregnant women with vaginal

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 19/22 infections. The percentage of pregnant women treated with Fluomizin is estimated at 20% to 25%. Considering the total number of patients exposed since Fluomizin has been on the market, an estimated 1.1 to 1.5 million pregnant women have been treated.

Four clinical studies (either performed by Medinova Ltd or published studies) involving 181 pregnant patients did not demonstrate any adverse effect on the pregnancy or on the foetus/ neonate. Two of these studies were specifically in pregnant women.

In one, the participants had an increased risk of miscarriage, based on their medical history; no miscarriages occurred in the Fluomizin group (Demina et al., 2005).

In the other study in pregnant patients (Grischenko et al, 2006b), placental dysfunction occurred in fewer patients treated with Fluomizin (29.4%) than in the control group receiving povidon-iodine (84.4%) in Week16 of pregnancy. The greatest differences between groups were found in the amount of amniotic fluid and placenta maturity. The author concluded that BV is accompanied by the development of placental dysfunction, causing high levels of pre-natal foetal hypoxia and perinatal pathology; effective treatment of bacterial vaginosis with Fluomizin in the first term of pregnancy provides favourable pregnancy conditions and perinatal outcomes.

In the two studies which included pregnant women with non-pregnant women (Fauner and Binder, 1974; Study FLU399), dequalinium chloride was well tolerated and no adverse drug reactions were reported.

One adverse event related to the pregnancy or the health of the foetus / new-born child was reported. A 30-year old patient who had received Fluomizin during her pregnancy experienced a miscarriage.

The causality was assessed by the treating gynaecologist as ‘not related’ to Fluomizin, based on the medical history and available safety profile of Fluomizin. There was no close time correlation between Fluomizin therapy and the miscarriage and the patient had a vaginal infection, for which there is a proven association to miscarriages and pre-term births. The miscarriage was considered most likely to be due to the pre-existing high risk and the vaginal infection.

In addition, the pharmacovigilance database includes three spontaneous adverse drug reactions from pregnant women; all were ulcers of the vulva or portio.

Conclusions: pregnancy and lactation The Applicant amended the wording regarding the use during pregnancy as requested.

In addition, the Applicant proposed a safety margin regarding the use of Fluomizin shortly before birth.

Patients aged <18 years According to the Applicants’ initial application, Fluomizin is not to be used by young girls who have not reached sexual maturity, as stated in the SPC. The rational for this consideration – especially in light of the patients included in the study – required further justification. The Applicant proposed to include all women who had their first menstruation. The RMS considered this approach questionable and proposed to state in section 4.4 of the SPC that no data on women aged less than 18 years are available. The Applicant amended the SmPC accordingly.

Patients aged >50 years/ post-menopausal women In older women, including those who are post-menopausal, dryness of the vaginal epithelium or other physiological changes may make them more susceptible to local adverse reactions to Fluomizin. There were no patients aged >55 years in Study 380104 but in Study FLU193 there were 18 participants aged between 51 and 68 years. Only minor, local adverse events occurred in this study and there was no indication that older women are at greater risk of clinically important events.

Fluomizin 10 mg Vaginaltabletten, DE/H/2422/001/DC Public AR 20/22

In Study FLU399, the study of normal clinical practice, 58 women aged between 51 and 78 years participated, suggesting that Fluomizin is generally used in this age-group to treat vaginal infections including BV.

Evaluation of spontaneous adverse event reports suggests that older women may be more at risk of vaginal ulceration associated with Fluomizin treatment. No other particular problem of safety or tolerability has been identified for this age-group but this will continue to be monitored by means of routine pharmacovigilance.

The sought indication is BV. According to the Note for Guidance on antibacterial agents (CPMP/EWP/558/95 rev 1) efficacy and safety results may be transferred from one patient population to a second patient population. Precondition for this strategy is an identical aetiology and comparable safety expectations in both groups. Thus, the Applicant should substantiate that the disease BV occurs in elderly women although vaginal flora is significantly different from younger women. Otherwise (i.e. if BV is not a common disease in elderly women), inclusion of elderly in the SPC would result in off-label use of Fluomizin to treat non-BV vaginal infections.

The RMS considers that the data on the treatment of BV in elderly patients are not sufficient to exclude an increase in side effects or loss of efficacy due to a different hormonal status and vaginal flora. This issue now has been addressed in the SPC in a similar way as for the young women.

Follow-up measure: Post-approval in vitro study of the activity of Fluomizin against Atopobium vaginae

Pharmacovigilance system The applicant FGK Representative Service GmbH (FGK-RS) has provided documents that set out a detailed description of the FGK system of pharmacovigilance (Version 2.0 dated 21 May 2010). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The applicant has also provided a statement dated 29 April 2010 stating that any SOPs or agreements not yet finalised will be finalized and valid by 29 May 2010 and that the medicinal product applied for will not be placed on the market before these SOPs are final and valid and before the agreements are executed.

Provided that the SOPs are finalized as committed above, the RMS considers that the Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.

Risk Management Plan Article 8(3)(ia) of Directive 2001/83/EC informs about the inclusion of “a detailed description of the pharmacovigilance and, where appropriate, of the risk management system which the applicant will introduce.” The criteria for the necessity of a risk management plan (system) are outlined in part I section 3.4 of Vol. 9A Pharmacovigilance of The Rules Governing Medicinal Products in the European Union. This application does not fulfil the criteria for situations requiring an EU-RMP, particular since it is not a new active substance and there is no new safety risk. Hence, strictly speaking, submission of a RMP is not necessary. However, the MAH has initially provided the document “Risk Management Plan Fluomizin Vaginal Tablets, 10mg Dequalinium Chloride”, dated 10 March 2009. In part II section 3.4.1a) of Vol. 9A it is stated that “if the Applicant/Marketing Authorisation Holder has submitted a Risk Management Plan as part of the application dossier, the RMS will include an assessment of it in the Assessment Report.”.

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The RMP is in line with the RMP template.

Periodic Safety Update Report (PSUR) Dequalinium chloride has been marketed in Germany as Fluomycin N in the same composition since 1993 for the treatment of vaginal infections of bacterial and mycotic origin, against trichomoniasis and to achieve asepsis prior to gynaecological surgery and births. It has been approved in Switzerland as Fluomizin in the same composition since 2002 (MA no 55 919) for the treatment of fluor vaginalis of bacterial and mycotic aetiology (e.g. bacterial vaginosis and candidiasis). Hence, since the active substance is well-known, the first PSUR should be submitted two years after the date of MA.

IV. BENEFIT RISK ASSESSMENT Benefits The efficacy of Fluomizin in the treatment of BV is non-inferior to standard treatment. Due to the very low systemic exposure no serious systemic adverse events were reported as would be expected. The use of Fluomizin does not induce resistance in the causative agents or the normal flora. Thus, no loss of efficacy of antibiotics urgently needed for systemic treatment has to be expected. This might be an important advantage compared to the use of antibiotics in the treatment of BV.

Risks There are no serious safety concerns and a warning regarding vaginal ulcers after prolonged use or increased dose now is included in the SmPC and the PL.

Balance The Benefit/Risk ration of Fluomizin in the treatment of BV is considered positive. Fluomizin offers an additional treatment option in BV, a disease with a high recurrence rate. The application is approved. For intermediate amendments see current product information.

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