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PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board

in the Netherlands

Estradiol/Estradiol Norethisteronacetaat Kit 37.5 + 30/95, transdermal patch, 37.5 micrograms/24 hours +

30 micrograms/24 hours and 95 micrograms/24 hours Estradiol/Estradiol Norethisteronacetaat Kit 50 + 40/130,

transdermal patch, 50 micrograms 24 hours + 40 micrograms/24 hours and 130 micrograms/24 hours

Sandoz B.V., the Netherlands

estradiol/estradiol + norethisterone acetate

This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report comments on the registration dossier that was submitted to the MEB and its fellow –organisations in all concerned EU member states. It reflects the scientific conclusion reached by the MEB and all concerned member states at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. General information on the Public Assessment Reports can be found on the website of the MEB. To the best of the MEB’s knowledge, this report does not contain any information that should not have been made available to the public. The MAH has checked this report for the absence of any confidential information.

EU-procedure number: NL/H/1156/001-002/MR

Registration number in the Netherlands: RVG 29686, 29687

16 March 2011 Pharmacotherapeutic group: progestagens and estrogens, fixed combinations ATC code: G03FA01 Route of administration: transdermal Therapeutic indication: hormone replacement therapy (HRT) for oestrogen deficiency

symptoms in postmenopausal women with uterus and more than 1 year postmenopause

Prescription status: prescription only Date of first authorisation in NL: 3 November 2006 Concerned Member States: Mutual recognition procedure with DE Application type/legal basis: Directive 2001/83/EC, Article 8.3

For product information for healthcare professionals and users, including information on pack sizes and presentations, see Summary of Product Characteristics (SPC), package leaflet and labelling.

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I INTRODUCTION Based on the review of the quality, safety and efficacy data, the member states have granted a marketing authorisation for Estradiol/Estradiol Norethisteronacetaat Kit 37.5 + 30/95, 37.5 micrograms/24 hours + 30 micrograms/24 hours and 95 micrograms/24 hours, and Estradiol/Estradiol Norethisteronacetaat Kit 50 + 40/130, transdermal patch, 50 micrograms 24 hours, 40 micrograms/24 hours and 130 micrograms/24 hours, from Sandoz B.V. The date of authorisation was on 3 November 2006 in the Netherlands. The product is indicated for hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with an intact uterus and more than 1 year postmenopausal. Experience treating women older than 65 years is limited. A comprehensive description of the indications and posology is given in the SPC. Each product consists of two patches, a patch with only estradiol and a patch with estradiol and norethisterone acetate: 1. ‘Low dose’: Estradiol 37.5 (EST 1), Estradiol + NETA Comb (EST/NETA 1) 37.5 + 30/95;

The release rate of estradiol in EST 1 is about 37.5 µg/day, release rate of EST/NETA 1 is about 30 µg EST/day and 95 µg NETA/day.

2. ‘Standard dose’: Estradiol 50 (EST 2), Estradiol + NETA Comb (EST/NETA 2) 50 + 40/130;

The release rate of estradiol in EST 2 is about 50 µg/day, release rate of EST/NETA 2 is about 40 µg EST/day and 130 µg NETA/day.

The combination matrix patches are identical in composition and are only different in size and content of active ingredients. The patches should be applied twice weekly. One treatment cycle of Estradiol/Estradiol Norethisteronacetaat Kit consists of 4 patches of transdermal estradiol (white sachets) followed by 4 patches of transdermal estradiol and norethisterone acetate (orange/light-blue sachet). Estradiol The active ingredient, synthetic 17ß-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women and alleviates menopausal symptoms. Norethisterone acetate As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women. This mutual recognition procedure concerns a full application with known active subtances based on article 8.3 of Directive 2001/83/EC. The pharmacological, toxicological and pharmacokinetic properties of the active substances are well-known. The clinical documentation in support of this application consisted of 2 pharmacokinetic studies (MKL 2844 and MKL 2772) and 2 clinical studies. Study 98-31-t-D-4 was the pivotal, 12-week, double blind, randomised, placebo- and reference-controlled study. This study was conducted with the ‘standard dose’ and ‘low dose’ patches proposed for marketing approval. This study had an open prolongation in order to assess efficacy and safety after one-year exposure. Study 98-32-t-D-5 was an uncontrolled study in which the safety and efficacy of the standard dose patch was evaluated over a period of one year. No scientific advice has been given to the MAH with respect to these products. No paediatric development programme has been submitted, which is acceptable in view of the therapeutic indication.

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II SCIENTIFIC OVERVIEW AND DISCUSSION II.1 Quality aspects Compliance with Good Manufacturing Practice The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for these product types at all sites responsible for the manufacturing of the active substances as well as for the manufacturing and assembly of these products prior to granting its national authorisation. Active substances The active substances are estradiol and norethisterone acetate, established active substances described in the European Pharmacopoeia (Ph.Eur.*). Estradiol is a white to almost white crystalline powder or colourless crystals. The substance is practically insoluble in water. Only one polymorphic form of estradiol hemihydrate is known. Norethisterone acetate is a white to yellowish white, crystalline powder. Two polymorphic forms are known in the literature. Only modification I is used. The CEP procedure is used for both active substances. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the new general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Manufacturing process CEPs have been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance Specifications for EST are those of the Ph.Eur. monograph with additional CEP requirements. These specifications are considered adequate to control the quality. Batch analysis results were presented for 5 batches meeting the drug substance specifications. For NETA the specifications are in line with the Ph.Eur. and CEP requirements. Batch results have been provided for 3 production scale batches. Stability of drug substance For the drug substance EST the re-test period of 5 years is stated on the CEP. With respect to NETA, sufficient stability data have been submitted to justify the re-test period of 4 years. * Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for substances are laid down by the authorities of the EU. Medicinal Product Composition KIT 37,5 + 30/95 Each patch of 15 cm2 (matrix system) in white sachet contains 3 mg EST (as estradiol hemihydrate) releasing 37.5 micrograms EST per 24 hours. Each patch of 20 cm2 (matrix system) in orange sachet contains 3.2 mg EST (as estradiol hemihydrate) and 16 mg NETA, releasing 30 micrograms EST and 95 micrograms NETA per 24 hours. KIT 50 + 40/130 Each patch of 20 cm2 (matrix system) in white sachet contains 4 mg EST (as estradiol hemihydrate) releasing 50 micrograms EST per 24 hours.

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Each patch of 27 cm2 (matrix system) in light-blue sachet contains 4.3 mg EST (as estradiol hemihydrate) and 21.6 mg NETA, releasing 40 micrograms EST and 130 micrograms NETA per 24 hours. The products are angular, transparent transdermal matrix patches with rounded corners located on an oversized removable protective liner. The patches are packed in white (EST 15 cm2/20 cm2), orange (EST/NETA 20 cm2) or light-blue (EST/NETA 27 cm2) sachets which are inserted into a carton. The sachet consists of (from the outer to the inner layer): paper, polyethylene foil, aluminium foil, polyethylene foil, and an attached polypropylene layer with moisture- and oxygen-absorbing properties. The patch is covered on the side of the drug containing adhesive matrix with a siliconised polyester foil. The excipients are: siliconised polyester foil (release liner); non siliconised polyester foil (backing foil); vitamin E preparation (USP), acrylic copolymer (matrix layer). Pharmaceutical development Formulation studies have been performed to reach optimal blood levels ensuring efficacy and safety. It was explained that a transdermal drug delivery system (TDDS) has been developed since the natural hormone estradiol is extensively metabolized after oral intake, the transdermal administration is the only way to avoid the first-pass metabolism in the liver. Different matrix concentrations were tested. Numerous developmental data for EST monopatches are similar to those for the EST/NETA patches. Different absorbing materials for packaging have been tested for reducing humidity influences. Regarding the 24 hrs release of the active substance it should be mentioned that there is a high surplus of drug substance in the transdermal patch, only part of the content is released in vivo. The pharmaceutical development of the product has been adequately described. Manufacturing process The manufacturing process comprises the following steps: production of the drug-adhesive solution, production of the laminate, cutting of the laminate, and punching the TDDS/packaging into sachets. In an evaluation study manufacturing process parameters have been optimised. The lamination process is identified as the critical manufacturing step. In trials with varying these parameters the following items have been analysed: matrix weight, water content, and total related substances EST and NETA. In addition residual solvents and residual monomers have been determined. Sufficient validation data on critical manufacturing parameters have been presented demonstrating that the production scale manu-facturing process is well under control for ensuring the quality of the finished product regarding parameters like dissolution, content uniformity of both drug substances, related substances, residual solvents and residual monomers. Control of excipients Nearly all excipients used comply with Ph.Eur. or USP requirements. For the acrylic copolymer and polyester foil, not siliconized, in-house specifications are applied. These specifications are acceptable. Quality control of drug product Adequate release specifications for the TDDSs have been set. The specification includes tests for patch size, identification, average weight, uniformity of weight, uniformity of dosage units, peel force, adhesive strength, water content, extraction rate, assay, related substances and microbial limit. Limits in the specification have been justified and are considered appropriate for adequate quality control of the product. The analytical methods have been sufficiently described. Batch results have been provided on 4 production batches of 30 µg+95 µg/20 cm2 and 4 production batches of 40 µg+ 130 µg/27 cm2. All results meet the set requirements. Stability of drug product

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Stability data on the product has been provided from five batches from each strength (15 cm2, 20 cm2 and 27 cm2) in accordance with applicable European guidelines demonstrating the stability of the product for two years. The following storage conditions need to be included in the SPC and on the label: Do not store above 25°C and Store in the original package. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded. II.2 Non-clinical aspects The pharmacological, toxicological and pharmacokinetic properties of the active substances are well-known. The following biological aspects of the transdermal patches were evaluated: local tolerance, dermal sensitization, phototoxicity and photosensitizing studies with the drug-containing adhesive matrix an acrylic copolymer, and the patch system with or without the active compounds. No safety issues arose from these studies. This excipient has been replaced through variations NL/H/1156/001-002/IB/002 and IB/003 (see table on page 24). Both active substances are available on the European market. The expert report gives an adequate review of the data published in open literature and the 23 additional studies, which were performed by the MAH. Given the experience with the product, registration can be granted from preclinical point of view. Environmental risk assessment The MAH has included an extensive environmental risk assessment. A large amount of both active substances will remain in the waste product. As with other hormone containing products a risk to the environment cannot be excluded. II.3 Clinical aspects II.3.1 Quality of clinical studies, compliance with GCP The MEB has been assured that GCP standards were followed in an appropriate manner in the studies conducted. II.3.2 Pharmacokinetics The MAH submitted a pivotal (MKL 2844) and a supportive (MKL 2772) pharmacokinetic study. Pivotal study MKL 2884 Study MKL 2844 is a multiple dose bioequivalence study with estradiol patches and estradiol/NETA patches proposed for marketing approval to examine dose-proportionality and relative bioavailability in the patches compared to Estraderm TTS 50 (Novartis, Germany) and Evorel conti (Janssen-Cilag UK). The study had a six-way cross-over design. A total of 36 post-menopausal females (aged 45-70) were included. Each treatment consisted of the application of 3 patches at day 1, 5, and 8 followed by a 7 days wash out period. Table 1. Description of patches and treatments used in study MKL 2844

Treatment a B c d e f Name EST 1 EST 2 EST/NET

A 1 EST/NETA

2 Estraderm

® Evorel®

Conti Type matrix Matrix matrix matrix reservoir Matrix Size (cm2) 15 20 20 27 10 16 ESTRADIOL CONTENT 3 mg (2.5

%) 4 mg (2.5

%) 3.2 mg (2

%) 4.3 mg (2

%) 4 mg 3.2 mg

ESTRADIOL NOMINAL RELEASE RATE

37.5 μg/day

50 μg/day 30 μg/day 40 μg/day 50 μg/day 50 μg/day

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NETA CONTENT - - 16 mg (10 %)

21.6 mg (10 %)

- 11.2 mg

NETA NOMINAL RELEASE RATE

- - 95 μg/day 130 μg/day - 170 μg/day

• The EST 2 Patch is equal to Estramon, a generic patch marketed by the MAH in Germany. • The Estraderm TTS 50 patch is a reservoir based transdermal system and has a release rate of 50

μg/day of EST and is marketed by Novartis in the Netherlands alone (RVG 12482) or in combination with Estragest TTS patches (reservoir based; 50 μg/day estradiol and 0.25 mg/day norethisterone acetate). The combination of these two patches is registered as Estracomb TTS (RVG 15415). The Estraderm TTS patches have no NETA component and therefore this innovator product can only be used to assess estradiol pharmacokinetics.

• The Evorel conti patch is registered in Italy, but not in the Netherlands. The Evorel Conti patch is matrix-based and has a release rate of EST of 50 μg/day and of NETA of 170 μg/day.

Bioequivalence with an innovator product is not required for the products EST/NETA 30/95 and 40/130, as both doses and administration schedules are different from existing treatments and as this application is supported by a clinical dossier. However, a valid comparison of the pharmacokinetics should be made with a valid reference product to enable an estimation of release rate. See tables 2-6 below for the pharmacokinetic parameters of the different patches. Table 2. Pharmacokinetic parameters (mean ± SD) of estradiol

Treatment a b c d e f Name EST 1 EST 2 EST/NETA

1 EST/NETA

2 Estraderm

® Evorel®

Conti AUC0-96 (pg/ml*h)

2398 ± 2505

3817 ± 2809

2029 ± 1397

2741 ± 1286

2850 ± 1271

1733 ± 996

Cav0-96 (pg/ml) 25 ± 26 40 ± 29 21 ± 15 29 ± 13 30 ± 13 18 ± 10 Cmax0-96 (pg/ml) 38 ± 42 59 ± 42 33 ± 23 43 ± 21 63 ± 28 30 ± 16 CMIN0-96 (PG/ML)

14.5 ± 13.5

22.4 ± 20.1

11.1 ± 6.8 16.6 ± 9.5 10.6 ± 8.5 10.6 ± 7.4

PTF0-96 0.92 ± 0.31

1.00 ± 0.38

1.10 ± 0.56 0.99 ± 0.40 1.82 ± 0.54

1.17 ± 0.61

tmax (h)* 12 (86) 12 (96) 12 (87) 18 (58) 36 (17) 12 (101) Values corrected for baseline; N=36; *median (CV)

Table 3. Pharmacokinetic parameters (mean ± SD) of estrone

Treatment C d Ratio c/d# Name EST/NETA 1 EST/NETA 2 AUC0-96 (pg/ml*h) 1533 ± 1222 2387 ± 1014 0.47 (0.03-1.79) Cav0-96 (pg/ml) 16 ± 13 25 ± 10 0.47(0.03-1.81) Cmax0-96 (pg/ml) 24 ± 14 35 ± 15 0.62 (0.14-1.58) CMIN0-96 (PG/ML) 10.0 ± 11.1 12.9 ± 7.1 0.90 (0.00-4.74) PTF0-96 0.65 ± 0.21 0.65 ± 0.21 0.58 ± 0.25 tmax (h)* 48 (33) 24 (25) Values corrected for baseline; N=18; *median (CV); #Geometric mean (min-max)

Table 4. Pharmacokinetic parameters (mean ± SD) of norethisterone

Treatment C d F Name EST/NETA 1 EST/NETA 2 Evorel® Conti AUC0-96 (pg/ml*h) 25043 ± 17500 32952 ± 15286 23082 ± 13835 Cav0-96 (pg/ml) 262 ± 183 344 ± 160 241 ± 145 Cmax0-96 (pg/ml) 341 ± 248 449 ± 204 315 ± 199 CMIN0-96 (PG/ML) 162 ± 102 231 ± 126 171 ± 104 PTF0-96 0.65 ± 0.21 0.65 ± 0.21 0.58 ± 0.25

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tmax (h)* 24 (54) 24 (77) 24 (69) N=36; *median (CV)

Table 5. Comparative pharmacokinetics of estradiol (treatment a, b, c, d, e, f)

Variable 90 % confidence interval Point. Est % CV % a vs b (dose corrected) AUC0-96 (pg/ml*h) 71.4 - 93.9 81.3 38 Cav0-96 (pg/ml) 70.5 - 93.9 81.3 38 Cmax0-96 (pg/ml) 70.0 - 92.8 80.6 37 CMIN0-96 (PG/ML) 73.0 - 105.6 87.8 49 PTF0-96 79.2-99.5 88.8 30 a vs c AUC0-96 (pg/ml*h) 105.4-140.5 121.7 38.1 Cav0-96 (pg/ml) 105.4-140.5 121.7 38.1 Cmax0-96 (pg/ml) 100.8-133.6 116.0 37.4 CMIN0-96 (PG/ML) 118.1-170.7 142.0 49.3 PTF0-96 79.2-99.5 88.8 30.0 a vs f AUC0-96 (pg/ml*h) 112.9-150.4 130.3 38.1 Cav0-96 (pg/ml) 112.9-150.4 130.3 38.1 Cmax0-96 (pg/ml) 101.3-134.3 116.6 37.4 CMIN0-96 (PG/ML) 111.1-161.2 133.8 49.3 PTF0-96 73.0-91.8 81.8 30.0 b vs d AUC0-96 (pg/ml*h) 115.7-154.1 133.5 38.1 Cav0-96 (pg/ml) 115.7-154.2 133.6 38.1 Cmax0-96 (pg/ml) 116.3-154.2 133.9 37.4 CMIN0-96 (PG/ML) 102.7-149.7 124.0 49.3 PTF0-96 90.8-114.2 101.8 30.0 b vs e AUC0-96 (pg/ml*h) 104.3-139.0 120.4 38.1 Cav0-96 (pg/ml) 104.3-139.0 120.4 38.1 Cmax0-96 (pg/ml) 75.0-99.4 86.4 37.4 CMIN0-96 (PG/ML) 163.8-238.8 197.8 49.3 PTF0-96 48.1-60.5 54.0 30.0

Table 6. Comparative pharmacokinetics of estradiol and norethisterone (treatment c, d, f)

Analyte Variable 90 % confidence interval Point. Est % CV % c vs d (dose corrected) Estradiol AUC0-96 (pg/ml*h) 78.3-104.3 90.3 38.1 Cav0-96 (pg/ml) 78.3-104.4 90.4 38.1 Cmax0-96 (pg/ml) 81.8-108.4 94.2 37.4 CMIN0-96 (PG/ML) 64.3-93.7 77.6 49.3 PTF0-96 82.2-103.4 92.2 30.0 Norethisterone AUC0-96 (pg/ml*h) 85.0-103.9 94.0 26.0 Cav0-96 (pg/ml) 85.1-104.0 94.1 25.9 Cmax0-96 (pg/ml) 83.3-103.7 92.9 28.4 CMIN0-96 (PG/ML) 88.0-102.4 94.9 19.2 PTF0-96 87.7-112.3 99.2 32.2 c vs f Estradiol AUC0-96 (pg/ml*h) 92.8-123.6 107.1 38.1 Cav0-96 (pg/ml) 92.8-123.6 107.1 38.1 Cmax0-96 (pg/ml) 87.3-115.8 100.5 37.4 CMIN0-96 (PG/ML) 85.3-115.3 99.4 - PTF0-96 82.2-103.4 92.2 30.0 Norethisterone AUC0-96 (pg/ml*h) 92.2-112.7 101.9 26.0 Cav0-96 (pg/ml) 92.2-112.7 102.0 25.9 Cmax0-96 (pg/ml) 90.8-113.1 101.3 28.4

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CMIN0-96 (PG/ML) 87.7-102.1 94.6 19.2 PTF0-96 100.6-128.7 113.8 32.2.0

Supportive study MKL 2772 The second study (MKL 2772) is a dose-finding study with patches with several doses and patch sizes (3 different patches), and the innovator products. This is a supportive study, as the tested patches (a, b, c) differ from the patches to be marketed. A difference in plasma concentration-time and delivery profile of EST and NETA was observed between test and reference preparations, which is probably caused by the fact that the test patches and the Estraderm TTS patch/Estracomb patch have a different release controlling mechanism. The test patches (EST/NETA 1 and EST/NETA 2) are matrix based, while the Estraderm TTS patches are reservoir based. The exposure to NETA and EST (AUC and Cmax) was shown to be comparable between the EST/NETA 1 patch and the Evorel Conti Patch. Furthermore, the concentration-time curves of the Evorel Conti Patch is comparable with the EST/NETA 1 patch regarding both the NETA component and the EST component. The 90% confidence interval of the AUC and Cmax of both EST and NETA are within the 0.80-1.25 limits of acceptation of bioequivalence. In conclusion, sufficient reference is made with the test patches (EST/NETA 1 and EST/NETA 2) with innovator products. As the major aim of the studies is to describe an approximate delivery rate, with clinical efficacy and safety of the patches separately investigated, this approach is acceptable. II.3.3 Pharmacodynamics The MAH has not performed any pharmacodynamic studies, but instead provided literature references. As for both active ingredients the mechanism of action is known, the absence of pharmacodynamic studies is acceptable. II.3.4 Clinical efficacy The main documentation in support of the efficacy included 2 clinical phase III studies.

Study ID Design & Duration Pivotal study

98-31-t-D-4, Part I double blind, r, P-controlled, reference-controlled; 3 cycles

98-31-t-D-4, Part II double blind prolongation for 3 cycles switching placebo to active and open prolongation for 12 to 14 cycles

98-31-t-D-4, Part III open prolongation; 14 cycles Supportive study

98-32-t-D-5, Main study uncontrolled; 12 to 14 cycles 98-32-t-D-5, Prolongation prolongation; 14 cycles

• A pivotal, 3 month double blind, randomized, placebo- and reference-controlled study (Study 98-31-t-

D-4, Part I) was conducted by the MAH with the standard dose (EST/NETA 2) and low dose (EST/NETA 1) patches proposed for marketing approval (PART I). This study had a double-blind prolongation for 3 months and an open prolongation in order to assess safety and efficacy after a one-year exposure (Study 98-31-t-D-4, Part II) and following two years of exposure (Study 98-31-t-D-4, Part III). The double-blind, double dummy design was prolonged over 3 treatment cycles switching the placebo group to one of the two treatment groups followed by an open extension of 7/8 cycles. One additional group was treated in an open parallel design with a reference therapy (Evorel® conti, 16 cm2, 3.2 mg E2, 11.2 mg NETA (Janssen-Cilag LTD, UK)) over 13/14 cycles for descriptive comparison.

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• An open, prospective study conducted by the MAH assessed the safety and efficacy of EST/NETA 2 over a period of one year (Study 98-32-t-D-5, Main Study). This study had a prolongation for another year. Treatment was switched from EST/NETA 2 to EST/NETA 1 (Study 98-32-t-D-5, Prolongation).

Sample size

Study no No. of randomised patients No. of patients evaluated 98-31-t-D-4 451 353 98-32-t-D-5 381 381

II.3.4.1 Pivotal study 98-31-t-D-4 (Part I) Design

Method of administration The transdermal test products were applied twice weekly as continuous combined treatment; the transdermal reference product Evorel® conti, 16 cm2, 3.2 mg E2, 11.2 mg NETA (Janssen-Cilag LTD, UK) was also applied twice weekly. Inclusion/exclusion criteria The characteristics of the participants are in line with the Note for Guidance on the investigation of HRT. The most important inclusion criteria were female patients aged between 45 and 65 years with an intact uterus, with symptoms related to estrogen deficiency, with at least 5 moderate-to-severe hot flushes per day or 35 per week and the state of postmenopause confirmed by spontaneous amenorrhoea for at least 12 months or 6 months’ amenorrhoea with FSH levels >50 mlU/ml and estradiol levels <20 pg/ml, no abnormal findings in cervical histology (PAP < III), baseline endometrial histology that does not indicate insufficient material or hyperplastic or neoplastic endometrium or other findings (endometrial histology score 2-4). Important exclusion criteria included patients who received oral HRT in the course of the last 8 weeks or an implant in the course of the last 6 months or transdermal HRT (patch or gel) in the course of the last four weeks. Primary criterion for evaluation

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Mean percent change in ITT population in number of moderate and severe hot flushes per 24 hours (documented in patient diaries) from baseline to the end of the 3rd treatment cycle as compared to placebo. The primary endpoint is in accordance with the Note for Guidance on the clinical investigation of HRT. Secondary criteria for evaluation • Mean number of hot flushes • Severity of hot flushes • Modified Kupperman index • Responder rates

Responder is defined as no occurrence of moderate and severe hot flushes • Urogenital symptoms

Urogenital symptoms were represented by frequent desire to urinate, urorrhoea, urinary incontence, and micturition complaints. Vaginal discomfort was represented by itching, burning, organic sensation. Each parameter was assessed by its intensity from 0=absent to 3=severe.

• Overall efficacy of treatments: This parameter was assessed by the patients and by the investigators at the end of the 3rd cycle using a 5-point scale from 1=very good to 5=very bad.

Results primary endpoint The ITT population (= all randomised patients who applied study medication at least once and had any data for hot flushes) comprised 353 patients: n=106 EST/NETA 1 (low dose), n=100 test EST/NETA 2, n=42 placebo, n=105 reference treatment. Mean percentage reduction rates were 93% in the standard dose group, 94% in the low dose group, and 67% in the placebo group. Differences versus placebo were highly significant (p<0.0001). In the reference group, the mean percentage reduction rate was 93%. Results secondary endpoints • Mean number of hot flushes In the standard dose group the mean number of hot flushes per 24 h decreased from 8.1 at baseline to 0.6 after the 3rd cycle. The low dose group showed a decrease from 7.8 to 0.5. In the placebo group the mean number of hot flushes at baseline was 8.8 and after three cycles 3.1. In the subgroup of women with 7 or more HF at baseline, the mean number of HF per 24 h decreased from 10.7 at baseline to 0.8 (standard dose), to 0.6 (low dose), and to 4.2 after the 3rd cycle (placebo). • Severity of hot flushes The mean percentage reduction in severity after the completion of the 3rd cycle was 92% in the standard dose group, 93% in the low dose group, and 68% in the placebo group (p<0.0001 for both comparisons, standard dose and low dose versus placebo). • Modified Kupperman index The mean baseline values in the ITT population were 30.2 in the standard dose group, 29.6 in the low dose group, and 31.6 in the placebo group. After the completion of the 3rd cycle (visit 3) the mean values reduced to 8.7 in the standard dose group, 7.9 in the low dose group, and 16.1 in the placebo group (p=0.0005 standard dose vs. placebo, and p=0.0003 low dose vs. placebo). • Responder rates After the completion of the 3rd cycle in the standard dose group 66.7% of the patients reported no hot flushes (‘responder’). In the low dose group the responder rate was 59.2%, and in the placebo group the rate was 20% (p<0.001 for both comparisons, standard dose and low dose vs. placebo). • Urogenital symptoms

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There was a tendency towards higher percentages for absence of symptoms and towards lower percentages for mild, moderate, and severe symptoms during the course of the study in all active treatment groups and less pronounced in the placebo group. • Overall efficacy of treatments Very good and good results were achieved by 93.4% of patients in the low dose group (test 1), by 91.8% of patients in the standard dose group (test 2), by 60.9% of patients in the placebo group, and by 87.5% of patients in the reference group. Corresponding results for the investigators were: 88.7% (test 1), 89.8% (test 2), 61% (placebo) and 88.5% (reference). II.3.4.2 Pivotal study 98-31-t-D-4 (Part II and III) The double blind, double-dummy design was prolonged over 3 treatment cycles switching the placebo group to one of the two active treatment groups, followed by an open extension of 7/8 cycles. Additionally, one group was treated with reference therapy over 13/14 cycles for the purpose of descriptive comparison. Efficacy was analysed by the mean change in modified Kupperman index from baseline, by the change in presence and intensity of urogenital symptoms and vaginal discomfort from baseline and by the overall efficacy judged by the investigator and the patients. A total of 131 patients receiving the low dose, 118 patients receiving the standard dose and 101 patients receiving the reference treatment completed the study. In the ITT population the mean reduction of Kupperman index from baseline to visit 6 (one-year treatment) was 26 and 31 in the low dose group and in the placebo/low dose group, respectively. In the standard dose group and in the placebo/standard dose group the reduction was 26 and the reference group showed a reduction of 27. Patients, who switched from placebo to active treatment showed a mean improvement from visit 3 (after the 3rd treatment cycle) to visit 4 (in the 6th/7th treatment cycle) which outcome was comparable to patients under active treatment (test 1 low dose / test 2 standard dose) when evaluating the period from baseline until visit 3. The most important improvement took place during the first three cycles under active treatment, the further development showed marginal tendencies, and the effect of the active treatment persisted over the whole study period. Concerning urogenital symptoms and vaginal discomfort, the tendency towards higher percentages for absence of symptoms and towards lower percentages for mild, moderate, and severe symptoms during the course of the study was obvious in all active treatment groups. Overall efficacy assessments were made at visit 3, 4, and 6 using a 5-point rating scale (from 1=very good to 5=very bad). In the active treatment groups the majority of ratings fell in the category "good" or "very good" for patients as well as for investigators (≥95% at visit 6). II.3.4.3 Supportive study 98-32-t-D-5 Design An open multicentre phase III study over 12-14 treatment cycles of 28 days each with standard dose only has been conducted in postmenopausal women on the safety of the new sequential transdermal HRT as a primary objective. Inclusion/exclusion criteria Inclusion and exclusion criteria were generally identical to the pivotal study with the exception of a defined number of hot flushes at baseline. Patients had to have symptoms related to estrogen deficiency. Secondary efficacy endpoints The secondary objectives included the mean number of hot flushes per 24 hours (first 3 treatment cycles), the change in the severity of hot flushes (first 3 treatment cycles), the mean change in modified Kupperman index from baseline to the whole observation period, the change in presence and intensity of urogenital symptoms and vaginal discomfort, and the overall efficacy as judged by the investigator and the patient. The ITT population consisted of all patients who applied the study medication at least once and had any data for hot flushes (HF) after baseline with a screening period of at least 4 days length (n=381,

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ITT1). For the ITT2 it was required in addition that patients should have an evaluable number of moderate to severe HF at baseline of 35 per week or higher, or 5/day for at least 4 days (n= 73, ITT2). Results For ITT1, the mean number of HF decreased from a mean of 3.2 to 0.3 (mean percentage change: 94%) and in the ITT2 population the mean number of HF decreased from 8.1 to 0.6 after the 3rd cycle (mean percentage change: 92%). The evaluation of the occurrence and intensity of climacteric complaints using a modification of the Kupperman index showed a clear decrease over the first three months of treatment. This effect could be maintained over the whole treatment period of about one year. At baseline, the Kupperman index had a mean value of 24.10 in the ITT1 population compared to a mean value of 2.29 at visit 6. The Kupperman index had a mean value of 28.56 in the ITT2 population compared to a mean value of 1.88 at visit 6 (end of treatment). Concerning urogenital symptoms and vaginal discomfort, the tendency towards higher percentages for absence of symptoms and towards lower percentages for mild, moderate, and severe symptoms during the course of the study was obvious in ITT1 as well as in ITT2. Overall efficacy assessments were made at visit 3, 4, and 6 using a 5-point rating scale (from 1=very good to 5=very bad). The majority of ratings fell in the category ‘good’ or ‘very good’ for patients as well as for investigators. Overall conclusion on efficacy in reduction of daily hot flushes The low and the standard dose groups showed sufficient and maintained (one year) efficacy in the reduction of symptoms related to estrogen deficiency, being consistently superior to placebo to a clinically relevant extent. Although this study was not primarily designed to compare active treatment groups, the results on all three active treatment groups suggested similar results. Results on the open supportive study were in agreement with the findings on the standard dose group of the pivotal study. II.3.4.4 Bleeding pattern/Amenorrhoea rate for EST/NETA 1 and EST/NETA 2 Studies of the MAH were conducted between 1999 and 2002 and evaluated as defined in the protocol. The evaluation of bleeding patterns was based on literature information; there was no guidance with respect to analysis of bleeding pattern in the European core SPC at that time. The definition of amenorrhoea was based on the concept of bleed-free cycles, with or without spotting, which was also used in the literature. The database was not planned to include information about amenorrhoea without spotting. New analysis in agreement with the European core SPC: Amenorrhoea rates defined as no bleeding/no spotting have been calculated. All bleeding analyses were only performed for "completers", i.e. all patients who documented at least 12 cycles under treatment. The evaluation also included the number of days with bleeding, here “no bleeding” was considered separately from “spotting”. Bleeding pattern for EST/NETA 1, Study 98-31-t-D-4, Part II The amenorrhoea rate and the number of days with bleeding are depicted below in comparison to the reference patch (Evorel® conti).

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“Spotting” did not require sanitary protection. Overall, the majority of women experienced scheduled bleeding episodes within the one-year observation period. Bleeding pattern for EST/NETA 2, Study 98-32-t-D-5 The amenorrhoea rate and the bleeding pattern per reference period are shown in the following tables.

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Over conclusion on bleeding pattern Standard dose: Amenorrhoea (no bleeding or spotting) was seen in 47.1% of the women (about 93% treatment naive, median 2.8 years postmenopausal) during months 10-12 of treatment whereas the cumulative amenorrhoea rate increased from 47.1% in cycle 10 to 56.2% in cycle 12. Breakthrough bleeding and/or spotting appeared in 53.3% of the women during the first three months of treatment and in 52.9% during months 10-12 of treatment. The rate of amenorrrhoea observed for the standard dose patch falls within the lower range of the pattern reported with oral continuous combined HRTs and is considered acceptable. Low dose: Amenorrhoea (no bleeding or spotting) was seen in 33.9% of the women (about 90% treatment naive, median 2.4 years postmenopausal) during months 10-12 of treatment whereas the cumulative amenorrhoea rate increased from 33.9% in cycle 10 to 40.2% in cycle 12. Breakthrough bleeding and/or spotting appeared in 63.4% of the women during the first three months of treatment and in 66.1% during months 10-12 of treatment. Especially with the low dose, the percentages on amenorrhoea, breakthrough bleeding and spotting are not very favourable, but this is also the case with the 1 other estradiol + progestagen continuously combined patch available on the market (Estalis). Oral continuos combined combinations of estrogens + progestagens appear to have a better rate of amenorrrhoea. II.3.5 Clinical safety II.3.5.1 Patient exposure Data were obtained in 381 patients valid for safety in study 98-31-t-D-5 and in 451 patients (test 1 n=130, placebo/test 1 n=31, test 2 n=132, placebo/test 2 n=28, reference n=130) valid for safety in study 98-31-t-D-4, Part II. The maximum duration of observation was about one year (12-14 treatment cycles of 28 days each). In study 98-32-t-D-5, n=264 women completed a 1-year treatment. In study 98-31-t-D-4, Part II, n=118 women treated with Test 2, n=131 women treated with Test 1, and n=101 women treated with the reference treatment finished the study. II.3.5.2 Adverse events A total number of 215 adverse events after baseline was reported by 147 patients out of the 381 patients included in study 98-32-t-D-5. Thus 38.6% of the patients experienced at least one adverse event until the end of treatment. 35.3% of the observed AEs were judged as drug related (at least probable /likely). At least one drug related AE was documented in 64 (16.8%) of all patients. A total number of 388 adverse events was reported by 173 patients out of the randomised 451 patients under active treatment in study 98-31-t-D-4, Part II. Thus 38.4% of the patients randomised experienced

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at least one adverse event. The total incidence of AEs per patient until the end of active treatment, excluding AEs under placebo treatment, was 38.5% for low dose, 38.8% for standard dose, and 37.7% for reference treatment. 58% of the observed AEs were judged as drug related (at least probable/likely). At least one drug related AE was documented in 130 (28.8%) of all randomised patients. The total incidence of drug related AEs was 28% in the low dose, 32.5% in the standard dose and 25.4% in the reference group. • Deaths No cases of death have been reported in either the low or standard dose group. • Other serious adverse events The incidence and nature of SAEs appear to be in line with those known from approved HRTs. Twenty eight SAEs occurred in 24 patients in study 98-31-t-D-4, Part II, 11 in the low dose group (test 1), 2 in the placebo/test 1 group, 4 in the standard dose group, 1 in the placebo/test 2 group, and 10 in the reference group. For 18 SAEs, a relation to the study drug could not be denied, 4 of these SAEs were related to the study drug according to the investigators and the co-investigator (n=3 test 1 [excessive vaginal bleeding, cervix neoplasm, vaginal hemorrhage], n=1 reference treatment [cervix neoplasm]). Two patients, one in the test 1 group and one in the reference group, experienced endometrial hyperplasia after 6 months of treatment. These events were judged as unlikely related to the study drugs. Fourteen SAEs were observed in 10 patients in study 98-32-t-D-5. A relation to the study drug (Test 2) could not be denied for one patient with extreme hypertension judged as "unlikely" and for another patient with long-lasting heavy bleeding judged as "probably" related to study drug. • Adverse events leading to discontinuation

Reference Treatment AE Skin reaction Bleeding Rozenberg et al. NDA 20-870 study 202

Evorel® sequi/conti E2/NETA 50/140 E2/NETA 50/250

16.4% 15.0% 28.0%

7% no details, included in AE

7.2% no details, included in AE

Study 98-31-t-D-4, Part II

test 1 low dose test 2 standard dose reference

5.6% 8.8% 9.2%

0.6% 2.5% 0.8%

1.2% 4.4% 2.3%

Study 98-32-t-D-5 test 2 standard dose 8.1% 1.3% 4.7% The low incidence of discontinuations due to skin reactions, contributes to the acceptability of a relatively high incidence of drug related application site reactions in both test groups in study 98-31-t-D-4, Part II. The incidence of discontinuation due to bleeding with the standard dose compared to the low and the reference dose is somewhat high, but within an acceptable range. • Drug-related adverse events

Number of drug related AEs after baseline until EoT (N≥3), study 98-31-t-D-4 Body system

Description of AE

Test 1 low dose

Test 2 standard dose

Reference

N N* % N N* % N N* % Body as a whole abdominal pain 1 1 0.6 3 3 1.9 3 3 2.3 Cardiovascular system

hypertension 0 0 0 4 6 2.5 5 5 3.8

Nervous system headache 1 1 0.6 1 1 0.6 2 2 1.5 Skin and appendages

application site reaction

25 33 15.5 25 38 15.6 6 6 4.6

breast pain 8 10 5.0 9 9 5.6 8 8 6.2 Urogenital system

menorrhagia 2 2 1.2 7 9 4.4 1 1 0.8

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metrorrhagia 8 12 5.0 12 16 7.5 8 9 6.2 uterine neoplasm 3 3 1.9 2 2 1.3 4 4 3.1

N: number of subjects with at least one AE; N*: number of AEs The incidence and nature of AEs and drug-related AEs was similar in study 98-31-t-D-4, Part II and 98-32-t-D-5. The incidence of drug related application site reactions in both test treatment groups of study 98-31-t-D-4 was substantially higher compared to the reference group (16% vs. 5%, respectively). According to the MAH, this latter difference might be explained by the double dummy study design over 6 months for the test 1 and test 2 treatment groups; while the reference treatment arm of the study was open,and descriptive only. An incidence range of 5-6% for metrorrhagia across all active treatment groups during the first year of treatment with a continuous combined HRT product is acceptable. II.3.5.3 Endometrial safety For both studies conducted by the MAH, endometrial biopsies were taken at baseline, after 6 months and one year of treatment or at premature study termination, if the duration of treatment was at least 3 months. Biopsy results under treatment were analysed under different aspects: • Endometrial safety: evaluation for endometrial hyperplasia or malignant neoplasia • Overall endometrial safety: precise estimation of the incidence of hyperplasia or more serious adverse

endometrial outcomes according to European guidance • Endometrial response: comparison of endometrial score pattern after baseline and under treatment In order to fulfil the recommendations of the CHMP PtC on HRT, the data of the individual studies were pooled. At the time of the conduct and the analyses of the 2 studies no CHMP Points to Consider on hormone replacement therapy which specifically define the populations for the various analyses were available. In order to reflect the current CHMP Points to Consider on hormone replacement therapy, the inclusion criteria for patients in the meta-analysis of the endometrial biopsy results were defined as follows: − valid baseline biopsy, i.e. a score of 2 – 4, where baseline is defined as the last available biopsy

before the initiation of the respective treatment − evaluable biopsy result after one year of the respective treatment, i.e. either an endometrial score

2-8 or a biopsy with insufficient tissue for diagnosis but endometrial thickness < 5mm − biopsies with diagnosis of hyperplasia or carcinoma performed during the study, whatever the

duration of treatment II.3.5.3.1 Endometrial safety low dose Table 8 below describes the number of patients who satisfy these criteria and who were thus eligible for the meta-analysis. Clearly, the total number of patients included in the meta-analysis satisfies the sample size requirements stated in the Points to Consider document, where approximately 300 patients were considered to be sufficient to have 80% power to show that the frequency of endometrial events is less than 2%. Table 8. Patient disposition for the low dose meta-analysis – continuous treatment

Study Baseline visit / Biopsy results

Visit after 1 yr. of treatment / Biopsy results

Included in meta-analysis

Main study 98-31-t-D-4

V0 Score 2-4: 129

V6/7P Score 2-8: 101 insuff. material: 10 insuff. material, but endometrial thickness <5 mm: 2 missing/DO: 18

103

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Prolongation study 98-31-t-D-4

V6/7P: Score 2-4: 88

V11/12P Score 2-8: 64 insuff. material: 12 insuff. material, but endometrial thickness <5 mm: 10 missing/DO: 12

74

Study 98-32-t-D-5

V6/7P: Score 2-4: 237

V11/12P Score 2-8: 193 insuff. material: 13 insuff. material, but endometrial thickness <5 mm: 11 missing/DO: 31

204

Total 381 The calculated upper limit of the 95% confidence interval of 1.24%, based on a point estimate, is within acceptable limits (see table below).

II.3.5.4 Endometrial safety standard dose

The number of patients is sufficient according to the Points to Consider on HRT, as is the calculated upper limit of the 95% confidence interval of 0.81%, based on a point estimate of 0. II.3.6 Overall conclusion on clinical safety Adverse events, serious adverse events and deaths The overall incidence of adverse events (AEs) and serious adverse events (SAEs) was similar in the studies conducted by the MAH and appeared to be in line with published literature. Application site reactions were relatively frequently reported (up to 15.6%), but incidences were comparable to that with Estracomb (registered in NL) and the rate of discontinuations due to this AE were low. An incidence range of 5-6% for metrorrhagia across all active treatment groups during the first year of treatment with a continuous combined HRT product is acceptable. In the studies conducted by the MAH, one venous thrombo-embolic event has been reported, but the limited number of patients included and the relatively short study duration preclude drawing final conclusions on this rare SAE. Endometrial safety For the standard dose regimen, the incidence rate of endometrial hyperplasia or more serious outcome was zero (no cases of endometrial hyperplasia or endometrial cancer). The number of patients (n=367) is sufficient according to the Points to Consider on HRT, as is the calculated upper limit of the 95% confidence interval of 0.81%, based on a point estimate of 0.

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With respect to the low dose regimen, one case of endometrial hyperplasia (complex type) has been noted. The number of patients (381) is sufficient according to the Points to Consider on HRT. Additionally, the calculated upper limit of the 95% confidence interval of 1.24%, based on a point estimate of 0.26, is within acceptable limits. Discussion on benefit/risk The CMS considered the endometrial safety insufficiently demonstrated, due to a high number of missing end-of-treatment biopsies. According to the CMS, concerns remain that a safe endometrial outcome cannot be concluded in these patients, based on the data available up to now. Further, it was stated that the bleeding pattern was insufficiently studied and seems unfavourable, based on the available data. Agreement on these two issues could not be reached during the MRP, and therefore a CMD(h) referral was initiated on 21 December 2007. CMD(h) Referral Endometrial safety In response to the question raised on endometrial safety, the MAH provided a comprehensive overview of the number of biopsies taken and of those that were missing. It appeared that the number of missing biopsies in patients treated for more than 3 months with insufficient biopsy or without follow-up biopsy varied between 7% to 12%. The percentage of women with insufficient biopsies who had no endometrial thickness measured was less than 1%. The percentage of women with missing biopsy (repeated biopsy) and missing endometrial thickness measurement varied between 4.2% and 8.1%. The MAH has adequately reasoned that the number of missing endometrial biopsies reported is not outside that reported in published studies that investigated endometrial safety by endometrial biopsies. Moreover, taking into account that an endometrial biopsy is an invasive method which is painful and unpleasant for the patient, not all patients could be persuaded to undergo a final biopsy, especially at a time point when the patients had already made their decision to discontinue the study. Bleeding pattern The second issue raised, the seemingly unfavourable bleeding pattern, was addressed by means of new Per Protocol (PP) and Intent-to-treat (ITT) analyses, and comparison of the bleeding pattern of the product against the chosen reference products. Also, the clinical benefit of the patches was justified. With regard to the endometrial bleeding pattern, the continuous combined patches appear to have a less favourable bleeding pattern when compared to oral preparations. However, this appeared not to have led to an increase in discontinuations due to unacceptable bleeding pattern. Further, the longer postmenopausal period in the reference group may have favoured a higher rate of amenorrhoea as described in public literature. However, regarding available data of previous applications, there are not many data on bleeding patterns of estradiol-only patches combined with oral progestagens, as these are in fact all approved on bioequivalence data versus Estraderm. Therefore, the comparative data from previous applications are scarce, i.e. Estracomb (continuous sequential only) licensed nationally and Estalis Conti/Estalis Sequi approved by MRP (SE/H/148/01 and SE/H/149/01) are the only combined estrogen + progestin patches to which the patches can be compared. Compared to the figures presented in the Estalis SPC, that were based on completers only, the bleeding patterns noted are within the range of that reported for Estalis and Estalis Sequi, and have not led to an increase in discontinuations due to unacceptable bleeding pattern. The patches are therefore considered acceptable as long as the bleeding pattern to be expected is clearly stated in the SPC. CMD(h) conclusion The relative benefit/risk ratio of EST/NETA 30/95 (low dose) and EST/NETA 40/130 (standard dose) in the indication of ‘hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women with uterus and more than 1 year postmenopause’ can be considered positive. The pattern of adverse drug reactions (ADRs) observed during treatment with EST/NETA 30/95 (low dose) and 40/130 (standard dose) is considered typical for transdermal patches and, when indirectly compared, does not clearly deviate from that observed with other transdermal HRT patches.

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Adequacy in prevention of endeometrial hyperplasia by addition of transdermal NETA was considered sufficiently shown, according to the recommendations of the CHMP Points to Consider on HRT. The bleeding pattern observed especially with the low dose regimen is suggested to be less favourable that that observed for oral combined HRTs, but is considered to be in line with that noted for the only other combined oestradiol/NETA patch already approved by MRP SE/H/148/001 (Estalis). Risk management plan The combination of EST and NETA was first approved in 1996, and there is now more than 10 years post-authorisation experience with the active substances. The safety profile of EST and NETA can be considered to be well established and no product specific pharmacovigilance issues were identified pre- or post authorisation which are not adequately covered by the current SPC. The MAH has a pharmacovigilance system at their disposal, which is based on the current European legislation. Routine pharmacovigilance activities are sufficient to identify actual or potential risks and a detailed European Risk Management Plan is not necessary for this product. Product information SPC The SPC is in accordance with the wording of the core SPC for HRT and with SPCs of previously authorised estradiol products. Readability test The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test was carried out in two rounds with 10 participants each. The target of 80% correctly answered questions was achieved. It can be concluded that the readability of the leaflet is of an acceptable level. Some changes were made to the leaflet to improve the readability and comprehensibility. The readability test itself and the evaluation report are of an acceptable quality. There were sufficient questions about the critical sections. The conclusions are clear, concise and clearly presented. Furthermore, the following areas have been sufficiently covered: traceability, comprehensibility and applicability.

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III OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT The chemical-pharmaceutical information about the manufacturing, the quality requirements with regard to the substances and the finished product are sufficient within the framework of the European registration requirements. The pharmacological, toxicological and pharmacokinetic properties of the active substances are well-known. The expert report gives an adequate review of the data published in the literature and the 23 additional studies, which were performed by the MAH. No new preclinical data have been submitted, and therefore the application has not undergone preclinical assessment. The MAH submitted a pivotal (MKL 2844) and a supportive (MKL 2772) pharmacokinetic study. Sufficient reference is made with the test patches (EST/NETA 1 and EST/NETA 2) to the innovator products. As the major aim of the studies is to describe an approximate delivery rate, with clinical efficacy and safety of the patches separately investigated, this approach is acceptable. The low and the standard dose groups showed sufficient and maintained (one year) efficacy in the reduction of symptoms related to estrogen deficiency, being consistently superior to placebo to a clinically relevant extent. Although the pivotal study was not primarily designed to compare active treatment groups, the results on all three active treatment groups suggested similar results. Results on the open supportive study were in agreement with the findings on the standard dose group of the pivotal study. The pattern of adverse drug reactions (ADRs) observed during treatment with EST/NETA 30/95 (low dose) and 40/130 (standard dose) is considered typical for transdermal patches and, when indirectly compared, does not appear to clearly deviate from that observed with other transdermal HRT patches. The MAH has provided written confirmation that systems and services are in place to ensure compliance with their pharmacovigilance obligations. The SPC, package leaflet and labelling are in the agreed templates and are in agreement with similar products. In the Board meeting of 27 October 2005, a discussion was held on quality aspects of the patches, as well as on endometrial safety. These concerns were resolved prior to national registration. The MEB, on the basis of the data submitted, considered that adequate evidence of efficacy for the indication “hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women with uterus and more than 1 year postmenopause” has been demonstrated for Estradiol/Estradiol Norethisteronacetaat Kit 37.5 + 30/95, 37.5 micrograms/24 hours + 30 micrograms/24 hours and 95 micrograms/24 hours, and Estradiol/Estradiol Norethisteronacetaat Kit 50 + 40/130, transdermal patch, 50 micrograms 24 hours, 40 micrograms/24 hours and 130 micrograms/24 hours, as well as a satisfactory risk/benefit profile and therefore granted a marketing authorisation. Estradiol/Estradiol Norethisteronacetaat Kit 37.5 + 30/95 and Estradiol/Estradiol Norethisteronacetaat Kit 50 + 40/130 were authorised in the Netherlands on 3 November 2006. The MRP started on 20 September 2007. By the end of the MRP, 19 December 2007, the CMS considered the provided data on endometrial safety insufficient, and the bleeding pattern observed with the products unfavourable. As consensus could not be reached on these issues, a CMD(h) referral was initiated. During the CMD(h) referral, the MAH provided additional information to support the endometrial safety, and comparison of the bleeding pattern of the product against the chosen reference products. Also, the clinical benefit of the patches was properly justified. The CMD(h) referral ended positively on 14 March 2008. The concerned member state, on the basis of the data submitted, considered that Estradiol/Estradiol Norethisteronacetaat Kit 37.5 + 30/95 and Estradiol/Estradiol Norethisteronacetaat Kit 50 + 40/130 demonstrated adequate evidence of efficacy for the approved indication and a satisfactory risk/benefit profile, and has therefore granted a marketing authorisation.

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A European harmonised birth date has been allocated (6 March 1998) and subsequently the first data lock point for estradiol + norethisterone acetate is March 2009. The first PSUR will cover the period from March 2008 to March 2009, after which the PSUR submission cycle is 3 years. The date for the first renewal will be: 3 November 2011. The following post-approval commitments have been made during the procedure: Quality - medicinal product - The MAH committed to reformulate the composition within 2 years after Dutch registration including

replacement of the Duro-Tak 387-2353 copolymer by another acrylate copolymer without having the residual epoxy-monomers and maintaining the same drug release behaviour as well as same adhesive properties of the acrylic layer. This commitment has been fulfilled through variations NL/H/1156/001-002/IB/002-003 (see table on page 24).

- The MAH committed to re-evaluate the specification on total norethisterone acetate impurities when more results have become available.

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List of abbreviations ADR Adverse Drug Reaction AE Adverse Event ASMF Active Substance Master File ATC Anatomical Therapeutic Chemical classification AUC Area Under the Curve BP British Pharmacopoeia CEP Certificate of Suitability to the monographs of the European Pharmacopoeia CHMP Committee for Medicinal Products for Human Use CI Confidence Interval Cavg Average plasma concentration Cmax Maximum plasma concentration CMD(h) Coordination group for Mutual recognition and Decentralised procedure for

human medicinal products CV Coefficient of Variation EDMF European Drug Master File EDQM European Directorate for the Quality of Medicines EST Estradiol EU European Union GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice HF Hot flushes HRT Hormone Replacement Therapy ICH International Conference of Harmonisation ITT Intent-to-treat MAH Marketing Authorisation Holder MEB Medicines Evaluation Board in the Netherlands NETA Norethisterone acetate OTC Over The Counter (to be supplied without prescription) PAR Public Assessment Report Ph.Eur. European Pharmacopoeia PIL Package Leaflet PP Per Protocol PSUR Periodic Safety Update Report SAE Serious Adverse Event SD Standard Deviation SPC Summary of Product Characteristics TDDS Transdermal Drug Delivery System t½ Half-life tmax Time for maximum concentration TSE Transmissible Spongiform Encephalopathy USP Pharmacopoeia in the United States

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure

number Type of modification

Date of start of the procedure

Date of end of the procedure

Approval/ non approval

Assessment report attached

Submission of a new of updated Ph.Eur. Certificate of Suitability for an active substance or starting material/reagent/intermediate in the manufacturing process of the active substance; from a manufacturer currently approved.

NL/H/1156/001-002/IA/ 001

IA 13-11-2008 27-11-2008 Approval N

Change in the synthesis or recovery of a non-pharmacopoeial excipient (when described in the dossier)

NL/H/1156/001-002/IB/ 002

IB 30-12-2008 29-1-2009 Approval N

Replacement of an excipient with a comparable excipient.

NL/H/1156/001-002/IB/ 003

IB 30-12-2008 29-1-2009 Approval N

Change in the name of the medicinal product in Germany.

NL/H/1156/001-002/IB/ 004

IB 28-5-2009 27-6-2009 Approval N

Significant modifications of the SPC due to new quality, pre-clinical, clinical or pharmaco-vigilance data.

NL/H/1156/001-002/II/ 005

II 8-7-2010 7-1-2011 Approval N