PUBLIC ASSESSMENT REPORT

Decentralised Procedure

OeKolp Ovula Procedure Number: DE/H/3422/01/DC

Active Substance: , 0.03 mg

Dosage Form: Pessary

Marketing Autorisation Holder in the RMS, Germany: Dr. Kade/ Besins Pharma GmbH

Publication: 18.01.2018

TABLE OF CONTENTS

I RECOMMENDATION 4

II EXECUTIVE SUMMARY 4

II.1 PROBLEM STATEMENT 4 II.2 ABOUT THE PRODUCT 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 4 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. 5

III SCIENTIFIC OVERVIEW AND DISCUSSION 5

III.1 QUALITY ASPECTS 5 III.2 NONCLINICAL ASPECTS 6 III.3 CLINICAL ASPECTS 6

IV BENEFIT RISK ASSESSMENT 10

V RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION 11

V.1 ASSESSMENT OF USER TESTING 11

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 2/11

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal OeKolp Ovula product in the RMS INN (or common name) of the active Estriol substance(s): Pharmaco-therapeutic group G03CA04 (ATC Code): Pharmaceutical form(s) and Pessary strength(s): Reference Number for the DE/H/3422/01/DC Decentralised Procedure Reference Member State: DE Member States concerned: DK; FI; HU; NO; PL; SE Dr. Kade/ Besins Pharma GmbH Marketing Authorisation Holder Rigistrasse 2 (name and address) 12277 Berlin Germany

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 3/11

I RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for OeKolp Ovula in the local treatment of vaginal symptoms of deficiency in postmenopausal women, is approvable.

II EXECUTIVE SUMMARY

II.1 Problem statement Oekolp Ovula contain 0.03 mg estriol per pessary in a base of hard fat with emulsifier. The therapeutic indication applied for is local treatment of vaginal symptoms of estrogen deficiency in postmenopausal women.

Local estrogen-deficiency conditions primarily target internal and external genital organs and the lower urinary tract. Vaginal atrophy is a common symptom of postmenopausal estrogen depletion; the epithelial layer of the inner vaginal surface thins, the vaginal wall looses elasticity due to shrinkage of the connective tissue in the propria. In addition, the estrogen dependent perfusion of the vaginal wall and the associated moisturing decrease and parabasal and intermediate cells predominate in diagnostic vaginal smears. The extent of these changes largely corresponds to the degree of estrogen deficiency. Typical symptoms associated with these changes include vaginal dryness, irritation, pruritus, discharge.

Estrogen replacement therapy effectively reverses the described untoward changes. In case of menopausal hormone depletion only manifests in signs and symptoms of vaginal atrophy, treatment can be efficiently accomplished by intravaginal application of preparations containing or estriol.

Scientific Advice National scientific advice was provided by BfArM on 26.11.2007 and 15.05.2008. In these two meetings, the outline of a pharmacokinetic study and a placebo-controlled phase III study regarding the efficacy of Oekolp Ovula in the treatment of vulvovaginal atrophy in postmenopausal women was discussed.

II.2 About the product Thus decentralised procedure concerns Estriol 0.03 mg pessaries containing the active substance estriol, under the trade name Oekolp Ovula. Estriol is a natural and one of the three main produced in females. All estrogens are structurally related : estradiol (E2) is reversibly oxidised to (E1) and both E2 and E1 can be irreversibly converted to estriol (E3), which also originates directly from 16α-hydroxiandrostenedione.

The ATC code is G03CA04.

The posology recommended in the SPC is 1 pessary daily during the first 3 weeks and 1 pessary twice weekly thereafter. The pessaries should be introduced deeply into the vagina, preferably in the evening before going to bed.

II.3 General comments on the submitted dossier The dossier was submitted according to Article 10(3) of Directive 2001/83/EC, hybrid application. The reference product Ovestin 0,5 mg Ovula, pessary, was approved in Germany in 1981, MA no. 328.00.01. The MA holder of Ovestin is MSD Sharp & Dohme GmbH. Ovestin contains 0.5 mg estriol per pessary.

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 4/11

The application concerns the addition of a new strength to the existing MA for Oekolp forte Ovula 0,5 mg, MA no. 22684.00.00, MAH Dr. Kade Pharmazeutische Fabrik GmbH. Oekolp forte Ovula 0,5 mg contain 0.5 mg estriol per pessary and are approved on a national basis for the local treatment of deficiency symptoms after and for diagnostic purposes (for lightening up atrophic changes which are difficult to assess in a vaginal smear).

With regard to module 5, one pharmacokinetic study and one phase III study were submitted. There is also a considerable amount of literature on pharmacokinetics, pharmacodynamics, efficacy and safety of different vaginally administered estriol preparations which is discussed in the clinical overview. In addition, with regard to safety post-marketing data on Oekolp Ovula and other estriol containing products of the MAH are available.

This approach is accepted, and no further clinical data are required. The clinical overviews was well written and of acceptable quality.

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. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.

It is stated in the study reports of the 2 submitted clinical studies KAD 139 and KAD 140 that these studies were conducted in accordance with GCP and in agreement with the World Medical Association Declaration of Helsinki. There were no indications of GCP non-compliance during the assessment.

III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Introduction

The application for OeKolp Ovula, pessary, 0.03 mg estriol is a hybrid application according to Directive 2001/83/EC, article 10(3). In this application it is referred to Ovestin®, 0.5 mg, pessaries as reference medicinal product. On base of the applicant´s response document on the questions raised on Day 70 all points for clarification have been adequately resolved now.

Drug substance For the drug substance, estriol, the applicant has submitted a Certificate of Suitability of the European Pharmacopoeia has been presented. The holder of the certificate has declared the absence of use of material of human or animal origin in the manufacture of the substance. A re-test period has been stated in the CEP. The quality of Esriol is controlled sufficiently and can be accepted.

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 5/11

Drug Product The manufacturing process for the drug product is a non-standard process due to the low content of the drug substance in the drug product. Sufficient process validation data have been provided. The drug product specification covers the relevant parameters needed for this dosage form. The description of the analytical methods used is in general acceptable. Batch analysis data have been provided for three production scale batches which have also been used for process validation. Based on the stability data provided a shelf-life period of 36 months can be granted.

III.2 Nonclinical aspects

The medicinal product applied for contains 0.03 mg estriol instead of 0.5 mg estriol which is contained in the reference medicinal product Ovestin®, 0.5 mg, pessaries as well as in OeKolp® forte Ovula 0.5 mg marketed by Dr. Kade. The excipients of the medicinal products are identical; merely the amounts of hard fat and emulsifier differ marginally.

Given the fact that estriol was already well described in the middle of the 20th century, a very large amount of clinical information is available. The activity and tolerability of estriol administered orally or topically is well known in humans, and most existing preclinical tests were conducted many years ago. Extensive clinical experience has been acquired over more than 30 years and therefore estriol containing medicinal products can be considered as products with well established use (Directive 2001/83/CE).

Therefore, this preclinical dossier does not contain any new preclinical data.

The nonclinical overview, dated 16. November 2011, is based on bibliographical references and is adequate.

Concerning local tolerance, reference is made to clinical data. It is agreed that a nonclinical study to address local tolerability is not necessary because the excipients of the medicinal products are identical.

III.3 Clinical aspects

Pharmacokinetics

Study KAD 140

One monocenter open-label single-arm study (KAD 140) was conducted by the applicant to investigate the pharmacokinetics of estriol after single dose and multiple dose intravaginal administration of Oekolp Ovula pessaries containing estriol 0.03 mg.

Nineteen healthy postmenopausal women were included.

The main results are displayed in the following table:

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 6/11

The rate and extent of E3 absorption from the IMP was poor.

The study thus demonstrates that there was no accumulation after multiple dosing, but suggests a poorer rate and extent of E3 exposure after multiple dosing. A similar effect was reported in the literature and can probably be explained by the maturating effect of locally applied estrogen on the vaginal epithelium.

No control group treated with the currently approved higher dose strength of 0.5 mg estriol vaginal pessaries or cream was included. Based on a historical comparison of pharmacokinetic data of Oekolp Ovula with higher dosed estriol products for vaginal administration, it seems that systemic exposure is considerably lower with Oekolp Ovula, and consequently, no or at least fewer systemic adverse effects compared to higher dose strengths would be expected.

Estriol was determined in human plasma samples by RP LC-MS/MS methods. The range was between 5 and 1000 pg/mL. However, the LLOQ of 5 pg/ml is significant higher than 5 % of the Cmax values found in the study samples. Furthermore, the working range of the method is too wide for the analysis Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 7/11 of the study samples as the concentration ranges found in the study samples are covered by one QC sample (15 pg/ml), only. The performance of the study sample analysis is therefore not in line with the current Guideline on Bioanalytical Method Validation (EMEA/CHMP/EWP/192217/2009) but as this study can be considered as an exploratory study to distinguish between placebo and drug product, this can be accepted.

From the results of the validation studies can be concluded that the method has been adequate sensitivity, precision, accuracy and specificity/selectivity to determine estriol at the concentration levels expected in real samples. (For more information see Annex Bioanalytics)

Bibliographic data

Estriol is a metabolic end-product. Therefore, after administration to man it does not undergo significant structural changes, other than conjugation in the . Mainly inactive glucuronides and glucuronourinates and sulfates are formed which are rapidly excreted by the kidneys. Nearly all estriol (91%) is bound to albumin in plasma; 8% is unbound and less than 1% is bound to sex hormone-binding globulin (SHBG). When corresponding doses of estriol are administered vaginally and orally the concentrations of conjugated estriol are 4 – 24 times higher after oral administration. These differences are explained by the fact that vaginal application circumvents the first pass through the liver, where a large portion of estriol is immediately conjugated. After single vaginal application of 0.5 mg estriol about 15 – 20% of the applied dose is absorbed into the circulation unchanged and peak plasma levels are reached 1-2 hours after application. Baseline levels are reached after 24 hours the latest. Plasma concentrations may vary depending on pharmaceutical form (cream, suppositories, vaginal tablets) and peak concentrations of estriol in the range from 50 to 300 pg/ml may be detected. After three weeks of daily vaginal administration of 0.5 mg estriol, average plasma levels can be expected to decrease by up to 50%. One of the reasons of this effect is probably the proliferated vaginal epithelium. The reported half-life of vaginally applied estriol also varies depending on the applied pharmaceutical form: after vaginal application of 0.5 mg estriol in Ovestin® pessaries, of 1 mg in Ovestin® cream and 0.05 mg in Blissel® / Gelistrol® gel, half-lives have been reported to be 5 – 7, 6 – 9 and 1.5 – 3 hours, respectively.

Pharmacodynamics

No pharmacodynamic studies were submitted. Bibliographic data on pharmacodynamics of different vaginally administered estriol products are available.

Endogenous estrogens exist in a dynamic balance of metabolic interconversions and are largely responsible for the development and maintenance of the female reproductive system and for the female phenotype. Estriol is a metabolic end-product in this conversion chain and has the weakest estrogenic activity at the receptor level.

Similar to other estrogens, estriol binds to intracytoplasmatic receptors after diffusing across the cell membrane, and this estriol-receptor complex after penetrating the nuclear membrane binds to the estrogen response element (ERE) with subsequent activation of selective messenger RNA synthesis; proteins/enzymes produced via the latter effect regulate specific cellular hormonal activity.

Local application of estriol in proposed low doses is not supposed to have any systemic effects and the main pharmacodynamic targets are the organs of the lower urogenital tract, adjoining the administration site. However, at much higher oral doses administered twice daily estriol is known to provoke untoward estrogenic effects such as proliferation of the endometrium.

Clinical efficacy

KAD 139

One phase III study (KAD 139) was submitted. Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 8/11

Study design

In this randomised double-blind placebo-controlled multicenter study, a low dose of 0.2 mg estriol and a very low dose of 0.03 mg estriol administered intravaginally daily for 21 days and twice weekly thereafter for a total duration of treatmnet of 12 weeks was investigated. Postmenopausal women with a clinical diagnosis of atrophy, a vaginal maturation index < 40%, at least one symptom of vaginal atrophy (dryness, pain/a burning sensation, pruritus, discharge, cohabitation problems) rated ≥ 65 on the visual analogue scale (VAS) and vaginal pH value > 5 were included. The following 3 criteria of vaginal atrophy were defined as the primary efficacy endpoints: Rise in the maturation index, normalisation of the vaginal pH value and improvement in the subjective most bothersome symptom (MBS) of vaginal atrophy. Secondary efficacy parameters were the course of VMI, of vaginal pH and of the MBS as well as physicians evaluation of efficacy and responder rates. Safety was assessed on the basis of incidence of adverse events, sonographic evaluation of endometrial thickness and gynaecological examination.

Results

In total, 438 patients were randomised; 436 patients took study and 397 patients completed the study. The ITT population comprised of 436 patients who took study medication. With regard to baseline demographic and disease characteristics, no relevant imbalances were observed. Mean age was about 65 years of age and the mean BMI was about 26 kg/m².

With regard to the primary endpoints, the following results were observed for the estriol 0.03 mg pessaries:

In general, the results regarding secondary endpoints supported the primary analysis. In the responder analysis, patients with missing values were considered as non-responders. Thus, this analysis is considered as conservative regarding handling of missing values. Statistically significant and clinically relevant superiority of estriol 0.03 mg vaginal pessaries vs. placebo was observed. Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 9/11

Bibliographical data

A large number of clinical trials performed in the 1980s and 1990s with different estriol-containing products and galenical forms have demonstrated the efficacy of vaginal treatment of estrogen deficiency symptoms in postmenopausal women. The vast majority of studies showed comparable results and could convincingly demonstrate the therapeutic efficacy of local estriol on vaginal cytology as well as on estrogen deficiency symptoms like dry vagina.

Clinical safety

Safety data on Oekolp Ovula are available from the two clinical studies KAD139 and KAD 140. In addition, post-marketing data from Oekolp Ovula and literature data on other intravaginally applied estriol preparations are available.

The most frequent AEs in the 2 clinical studies submitted and reported in the post-marketing data were local reactions such as burning (6.8%) and pruritus (1.4%) at the application site.

The endometrial thickness was measured at screening and after treatment (follow-up) in trial KAD 139 by means of sonography. Before estriol treatment, the endometrial thickness was less than or equal to 5 mm in all subjects. After treatment, the endometrial thickness of three subjects (one in each treatment group) was more than 5 mm.

Taking also the available post-marketing data into account, there are currently no indications that administration of Oekolp Ovula is associated with systemic adverse effects.

Pharmacovigilance system

The applicant has provided documents that set out a detailed description of the Dr. Kade system of pharmacovigilance. 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 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

An EU risk management plan (EU-RMP) due to Article 8 (ia) of Directive 2001/83/EC, as amended, is not appropriate since the product applied for is a hybrid medicinal product. No safety concern requiring additional risk minimization activities has been identified with the reference medicinal product.

IV BENEFIT RISK ASSESSMENT

The efficacy of Oekolp Ovula containing 0.03 mg estriol per pessary in the treatment of vulvovaginal atrophy in postmenopausal women was shown in a double-blind placebo-controlled multicenter phase III study. Statistically significant as well as clinically relevant superiority vs. placebo was shown regarding signs such as vaginal maturation index and vaginal pH as well as regarding subjective symptoms such as vaginal dryness.

With regard to safety, mainly local reaction such as vaginal burning sensation and pruritus were observed. As for higher dosed estriol-containing products for intravaginal administration, concomitant Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 10/11 administration of a is not required. From the available post-marketing data, no new safety signals were detected.

The SPC and PL were revised as requested by the RMS and CMSs and are acceptable.

In summary, approval of Oekolp Ovula is recommended.

V RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION

V.1 Assessment of User Testing

The user testing is considered as successful and is accepted.

Oekolp Ovula DE/H/3422/01/DC Public Assessment Report 11/11