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Non-interventional study

BEDY1 Study

BELARA®

Evaluation on Dysmenorrhoea

Report Number: NIS-BEL-GE-04 English translation of German report (Final Version dated 27th Nov. 2007) 1 Belara® Evaluation on Dysmenorrhoea

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Belara® Observational Study

(Report No.: NIS-BEL-GE-04)

Final Version Page 2 of 99

27. Nov. 2007 Table of Contents LIST OF ABBREVIATIONS USED AND DEFINITIONS.............................................................6

1 SYNOPSIS ........................................................................................................................8

2 INTRODUCTION ...........................................................................................................16

2.1 Background.................................................................................................................16 2.2 Aim of the Evaluation .................................................................................................16

3 METHOD........................................................................................................................17

3.1 Study Procedure ..........................................................................................................17 3.2 Medication ..................................................................................................................17

3.3 Efficacy and Tolerability Parameters ...........................................................................18 3.4 Data Entry and Data Management ...............................................................................18

3.5 Statistical Evaluation...................................................................................................20 3.6 Calculation of the Pearl Index......................................................................................21

3.7 Analysed Random Samples .........................................................................................22

4 RESULTS ON THE EFFICACY OF BELARA® .............................................................25

4.1 General Study Outcome...............................................................................................25

4.2 General Patient Data....................................................................................................25 4.2.1 Morphometric Data .....................................................................................................25 4.2.2 Patient’s Occupation....................................................................................................27 4.2.3 Restarters ....................................................................................................................27 4.2.4 General Case History...................................................................................................28 4.2.4.1 Risk Factors............................................................................................................28 4.2.4.2 Previous Contraception...........................................................................................28

4.3 Treatment with Belara® ...............................................................................................31 4.3.1 Reason for Starting/Switching .....................................................................................31 4.3.2 Mode of Administration ..............................................................................................33 4.3.3 Regularity of Administration .......................................................................................34 4.3.4 Continuation or Termination of Belara® Treatment After 6 Cycles ..............................36

4.4 Course Findings ..........................................................................................................39 4.4.1 Duration of Observation ..............................................................................................39 4.4.2 Evaluation Population .................................................................................................40 4.4.3 Cycle Course...............................................................................................................40 4.4.3.1 Cycle Stability ........................................................................................................40

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27. Nov. 2007 4.4.3.2 Intensity of Withdrawal Bleeding............................................................................41 4.4.3.3 Absence of Menstruation ........................................................................................43 4.4.3.4 Intermenstrual Bleeding ..........................................................................................45 4.4.4 Dysmenorrhoea ...........................................................................................................47 4.4.4.1 Administration of Analgesics Due To Symptoms....................................................49 4.4.4.2 Absence From School or Work Due To These Symptoms.......................................51 4.4.5 Other Disorders ...........................................................................................................51 4.4.5.1 Premenstrual Syndrome ..........................................................................................51 4.4.5.2 Mood Swings..........................................................................................................53 4.4.5.3 Breast Tenderness...................................................................................................55 4.4.5.4 Headache ................................................................................................................57 4.4.5.5 Circulatory disturbances .........................................................................................59 4.4.5.6 Greasy/acne-prone Skin ..........................................................................................61 4.4.5.7 Greasy Hair ............................................................................................................63 4.4.5.8 Alopecia .................................................................................................................65 4.4.6 Weight, Blood Pressure and Pulse ...............................................................................67

4.5 Final Assessment.........................................................................................................68 4.5.1 Physician’s Assessment ...............................................................................................68 4.5.2 User’s Assessment.......................................................................................................70

4.6 Contraceptive Efficacy ................................................................................................72

4.7 Drug Exposure During Pregnancy (DEDP)/Return to Fertility.....................................73

5 RESULTS ON THE TOLERABILITY OF BELARA®....................................................74

5.1 Data Recording and Evaluation ...................................................................................74

5.2 Overview: reports/AEs/ADRs .....................................................................................75 5.3 Classification of ADRs as “serious” or “non-serious”..................................................77

5.4 ADR Frequency Distribution according to MedDRA® System Organ Classes .............77 5.5 ADR Frequency Distribution according to MedDRA® System Organ Classes in

Four Selected Subgroups .............................................................................................81

5.6 ADR Labelling............................................................................................................92

5.7 Synoptic Assessment ...................................................................................................95

6 MEDICAL BRIEF ASSESSMENT .................................................................................96

7 LITERATURE.................................................................................................................97

8 SIGNATURE PAGE FOR TRANSLATION ...................................................................98

9 LIST OF APPENDICES..................................................................................................99

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27. Nov. 2007

TABLE OF CONTENTS Table 4.2.1:1 Age of the patients (categorial).............................................................................................................. 25 Table 4.2.1:2 Weight (categorial) ............................................................................................................................... 26 Table 4.2.2:1 Occupation ........................................................................................................................................... 27 Table 4.2.4.1:1 Risk factors........................................................................................................................................ 28 Table 4.2.4.2:1 Last contraceptive method.................................................................................................................. 28 Table 4.2.4.2:2 Starter/Switcher ................................................................................................................................. 29 Table 4.2.4.2:3 Classification according to progestogens Preparation previously taken................................................ 29 Table 4.2.4.2:4 Classification according to preparation composition Preparation previously taken............................... 30 Table 4.3.1:1 Reason for starting/switching ................................................................................................................ 32 Table 4.3.2:1 Mode of administration of Belara® ........................................................................................................ 33 Table 4.3.2:2 Different mode of administration (extended cycle): time of pill-free interval.......................................... 33 Table 4.3.3:1 Regularity of administration.................................................................................................................. 34 Table 4.3.3:2 Regularity of administration.................................................................................................................. 35 Table 4.3.4:1 Continuation of administration of Belara® beyond the observation period of 6 cycles or 6 blisters .......... 36 Table 4.3.4:2 Reason for terminating treatment with Belara® ...................................................................................... 37 Table 4.3.4:3 Was the administration of Belara® terminated prematurely?................................................................... 38 Table 4.3.4:4 Reason for premature termination of treatment with Belara®.................................................................. 38 Table 4.4.1:1 Observation period (months)*............................................................................................................... 39 Table 4.4.3:1 Cycle course: cycle stability.................................................................................................................. 40 Table 4.4.3:2 Cycle course: cycle stability depending on starting/switching ................................................................ 41 Table 4.4.3.2:1 Cycle course: intensity of withdrawal bleeding (categorial)................................................................. 42 Table 4.4.3.3:1 Cycle course: absence of menstruation ............................................................................................... 44 Table 4.4.3.4:1 Cycle course: intermenstrual bleeding ................................................................................................ 46 Table 4.4.4:1 Dysmenorrhoea: symptoms during menstruation ................................................................................... 47 Table 4.4.4:2 Dysmenorhoea: intensity of these symptoms ......................................................................................... 48 Table 4.4.4:3 Dysmenorrhoea: symptoms during menstruation depending on starting/switching.................................. 49 Table 4.4.4.1:1 Dysmenorrhoea: adminstration of analgesics ...................................................................................... 50 Table 4.4.4.2:1 Dysmenorrhoea: absence from school/work due to these symptoms .................................................... 51 Table 4.4.5.1:1 Other disorders: PMS......................................................................................................................... 52 Table 4.4.5.2:1 Other disorders: mood swings ............................................................................................................ 54 Table 4.4.5.3:1 Other disorders: breast tenderness ...................................................................................................... 56 Table 4.4.5.4:1 Other disorders: headache .................................................................................................................. 58 Table 4.4.5.5:1 Other disorders: circulatory disturbances ............................................................................................ 60 Table 4.4.5.6:1 Other disorders: greasy/acne-prone skin ............................................................................................. 62

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27. Nov. 2007 Table 4.4.5.7:1 Other disorders: greasy hair................................................................................................................ 64 Table 4.4.5.8:1 Other disorders: alopecia.................................................................................................................... 66 Table 4.4.6:1 Vital parameters at baseline visit ........................................................................................................... 67 Table 4.4.6:2 Vital parameters at final visit................................................................................................................. 67 Table 4.5.1:1 Assessment of Belara®: physician’s assessment ..................................................................................... 69 Table 4.5.2:1 Assessment of Belara®: user's assessment.............................................................................................. 71 Table 5.2:1 Absolute and relative number of patients with NOAEs/AEs/ADRs ........................................................... 76 Table 5.4:1 List of the absolute and relative frequencies of ADRs............................................................................... 78 Table 5.5:1 List of the absolute and relative frequencies of ADRs............................................................................... 82 Table 5.5:2 List of the absolute and relative frequencies of ADRs............................................................................... 84 Table 5.5:3 List of the absolute and relative frequencies of ADRs............................................................................... 86 Table 5.5:4 List of the absolute and relative frequencies of ADRs............................................................................... 88 Table 5.5:5 List of the absolute and relative frequencies of ADRs............................................................................... 90 Table 5.6:1 Labelling of ADRs................................................................................................................................... 92 Table 5.6:2 Incidences of all labelled ADRs ............................................................................................................... 93

LIST OF FIGURES

Not applicable

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27. Nov. 2007 LIST OF ABBREVIATIONS USED AND DEFINITIONS

ABBREVIATIONS

Abbreviation Explanation ADR Adverse drug reaction AE Adverse event BMI Body mass index BfArM Bundesinstitut für Arzneimittel und Medizinprodukte

(Federal Institute for Drugs and Medical Devices) CI Confidence interval CCDS Company core data sheet CMA Chlormadinone acetate COC Combined oral contraceptive CPA Cyproterone acetate CRF Case report form DEDP Drug exposure during pregnancy EE Ethinylestradiol e.g. For example i.e. That is MedDRA® Medical dictionary for regulatory activities OC Oral contraceptive PMS Premenstrual syndrome PT Preferred term SD Standard deviation vs. versus

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27. Nov. 2007 DEFINITIONS Efficacy total population Population for whom prospectively recorded data are

available on the efficacy of Belara® Conventional cycle regimen (“normal cycle regimen”)

Medication regimen of a monophasic COC in which one tablet is taken daily for 21 days followed by a seven-day pill-free interval per cycle (28 days).

Starter A patient who before taking Belara® had either never used a hormonal contraceptive or had not used one at least in the last three months prior to the current Belara® medication.

No-adverse-event Cases in which a safety reporting form on suspected ADRs contains neither an AE nor an ADR

Safety population Population for whom Belara® tolerability data are available (data recorded prospectively and retrospectively)

Adverse drug reaction (= “side-effect”) (= “suspected ADR”)

means a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function.

Switcher A patient who in the last two months before taking Belara® had used a hormonal contraceptive

Adverse event is any untoward occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

Restarter after pregnancy/breast-feeding A patient who took Belara® after childbirth or after stopping breast-feeding.

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27. Nov. 2007 1 SYNOPSIS

Name of the sponsor: Grünenthal GmbH

German Division

Pascalstraße 6

52076 Aachen

Title of the observational study: Non-interventional study: Belara® evaluation on dysmenorrhoea

Abbreviated title: “BEDY”1

Trade name: Belara®

Active ingredients: 0.03 mg ethinylestradiol 2 mg chlormadinone acetate

Indication: Hormonal contraception

Dosage: The administration of Belara® per pill cycle was once daily for 21 days followed by a seven-day pill-free interval (conventional cycle regimen).

The administration of Belara® in an extended cycle regimen (administration of 2-6 blisters followed by a seven-day pill-free interval) was also documented.

Duration of observation period An observation period of 6 cycles or 6 blisters was recommended. There were two examinations (immediately before starting administration of Belara® and at the end of the observational study).

The observational study was carried out from August 2003 to November 2004 in Germany.

Aim of the observational study The aim of this observational study was to follow up the significance and changes in dysmenorrhoea and other symptoms in daily practice on administration of Belara® to a large group of women, thus extending the database regarding these effects.

Number of patients in the participating centres

4824 patients (310 of which were documented retrospectively) in a total of 608 centres (median: 8.0 patients per centre)

Patient populations: Patients desiring contraception, particularly with concomitant dysmenorrhoea.

The focus of the evaluation was on the efficacy total population. Moreover, additional evaluations were carried out with 4 different subgroups: (1) up to 19 years, (2) up to 19 years with dysmenorrhoea, (3) up to 24 years, (4) up to 24 years with dysmenorrhoea.

1 Belara® Evaluation on Dysmenorrhoea

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27. Nov. 2007 Number of patients: Efficacy total population: n = 4514 patients

Efficacy subgroup (1): ≤ 24 years, n = 2886

Efficacy subgroup (2): ≤ 24 years + dysmenorrhoea, n = 2376

Efficacy subgroup (3): ≤ 19 years, n = 1923

Efficacy subgroup (4): ≤ 19 years + dysmenorrhoea, n = 1644

Safety population: n = 4824 patients

The following parameters were documented The patient data were recorded over an observation period of approx. 6 cycles or 6 blisters in two recording sessions.

Parameters recorded:

Demographic and morphometric data

For restarters: date of childbirth, if applicable date of stopping breast-feeding

Risk factors in case history of the patient and her family

Reasons for starting/switching to Belara®

Date of first Belara® administration

Mode of administration

Regularity of administration

If applicable on termination of administration of Belara®: date and reason

Date of baseline and final visit

Information on cycle course: cycle stability, intensity of withdrawal bleeding, absence of menstruation and intermenstrual bleeding

Information on dysmenorrhoea: incidence and intensity of dysmenorrhoea, administration of analgesics due to dysmenorrhoea, absence from school or work due to dysmenorrhoea

Incidence and seriousness of other disorders: PMS, mood swings, breast tenderness, headache, circulatory disturbances , greasy/acne-prone skin, greasy hair, alopecia and other symptoms described in more detail by the physician

Blood pressure and pulse

Weight

Final assessment by physician and patient regarding reduction of skin problems and dysmenorrhoea, well-being and assessment of Belara® compared to the previous contraceptive

Adverse drug reactions

Efficacy parameters: Cycle course (before administration vs. at the end of the

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Final Version Page 10 of 99 27. Nov. 2007

observational study)

Dysmenorrhoea (before administration vs. at the end of the observational study)

Other cycle-related disorders (before administration vs. at the end of the observational study)

Final assessment

Contraceptive efficacy (Pearl Index)

Tolerability parameters Type, classification into "serious” and "non-serious" and incidence of adverse drug reactions

Statistical methods Analysis was based on descriptive methods only.

Absolute and relative frequencies, mean, standard deviation, first percentile, 25th percentile, median, 75th percentile and 99th percentile were calculated depending on the scale.

For the curve variables (cycle course, dysmenorrhoea, other disorders and vital parameters) descriptive p values were calculated for the changes in the course of the observational study using Wilcoxon rank test or McNemar’s test.

Demographic data The median age of the prospectively documented patients (n=4514) was 20.86 years. 3.63% of the patients were ≤ 14 years old, 41.05% between 15 and 19 years old, 23.59% between 20 and 24 years old and 30.73% were ≥ 25 years old. There were no details for 45 patients (1.00%).

The median height of the patients was 168.00 cm. The median body weight was 61.00 kg. The median body mass index (BMI) was 21.87 kg/m2.

According to age distribution 56.96% of the patients were still at school, students or were in professional training. 30.88% of the patients were employed, 10.61% were housewives and for 0.91% another occupation was stated. There were no details for 29 patients (0.64%).

History data With regard to existing risk factors 32.74% of the patients were smokers and 15.77% were overweight (BMI ≥ 25 kg/m2 or “overweight”). 1.91% of the patients had known thrombo-embolic diseases in the family and 1.17% reported other risk factors for taking the pill.

Previous contraception 64.55% of the patients took an oral hormonal contraceptive for the first time or had used a hormonal contraceptive for the last time more than 3 months ago. 25.92% of the patients switched from another oral contraceptive to Belara®. In 9.53% of the patients a classification was not possible (8.15% of the patients could not be classified due to the definition of starter and switcher and there were no details for 1.79%).

Reasons for prescription: Dysmenorrhoea and contraception were the most frequent reasons for starting Belara® treatment (66.35% and 62.01% of all prospectively documented patients, respectively). In

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47.63% of the patients skin/hair problems were reported, in 20.12% cycle irregularities and in 8.15% other reasons (multiple classifications possible).

Administration of Belara®: Usually tablets were administered for 21 days followed by a seven-day pill-free interval (normal mode of administration, 94.44% of the patients). Contrary to this 3.99% of the patients took Belara® in the extended cycle (in most cases with a pill-free interval after 3 blisters). 82.30% of the patients regularly took Belara®. Belara® was not taken regularly in 7.78% of the patients and there were no details for 9.92% of the patients. In patients with irregular administration of Belara® there was mostly one single omission of administration per cycle (68.66%). In 27.35% administration was forgotten several times per cycle.

In 86.26% of the patients administration of Belara® was continued beyond the observation period of 6 cycles or 6 blisters, in 12.30% of the patients administration was terminated at the latest after 6 cycles or 6 blisters. The most frequent reasons for termination or premature termination were persistent symptoms/intolerance (52.61% of the patients), patient no longer attended (14.95%) and contraception no longer desired (14.05%).

Duration of observation: The median observation period was 6.01 months.

The safety population comprised a total of 26 945.50 treatment cycles (2073 woman years).

The efficacy total population comprised a total of 25 166.00 treatment cycles (1936 woman years).

Contraceptive efficacy: For 6 patients pregnancy was documented during administration of Belara®. For the safety population (n = 4824) in an administration period of 26 945.50 cycles there was a practical Pearl Index of 0.289 (95% confidence interval (CI): 0.11 - 0.63). As none of the 6 pregnancies occurred on regular administration of Belara®, this resulted in a theoretical Pearl Index of 0 (95% CI: 0.00 - 0.18).

Non-contraceptive additional benefits:

Cycle course (cycle stability):

The following details on changes in the course of the observational study relate to the respective subgroups with valid details at the two recording times (baseline and final visit).

Regarding the cycle course the following changes occurred in the efficacy total population: the number of patients with a regular cycle increased distinctly whilst taking Belara®. After approximately 6 months’ administration the number of patients with a regular cycle increased from 66.70% to 98.09%, whilst the number of patients with an irregular cycle decreased from 33.30% to 1.91% (p ≤ 0.001). Whilst prior to administration of Belara® 26.01% of the patients had severe to very severe menstrual bleeding, at the final visit this was only the case in 0.94% of the patients. In the course of the observational study the number of patients with slight to moderate menstruation increased from

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Dysmenorrhoea:

Other disorders:

73.99% to 99.06% (p ≤ 0.001). Absence of single periods was less frequently observed whilst taking Belara® than before administration. Whilst prior to starting treatment with Belara® this was the case in 22.09% of the patients, at the final visit this was documented only in 6.92% (p ≤ 0.001). Frequent to very frequent absence of menstruation was stated at the final visit only in 0.50% of the patients compared to 5.77% prior to Belara® administration. On administration of Belara® there were fewer cases of intermenstrual bleeding in the course of the observational study. Whilst prior to starting treatment with Belara® intermenstrual bleeding occurred in 32.02% of the patients, at the final visit this was the case only in 15.21% (p ≤ 0.001).

In the course of the observational study there was a distinct reduction in the incidence and intensity of dysmenorrhoea. Whilst prior to starting treatment with Belara® 78.56% of the patients suffered from dysmenorrhoea, this was only the case in 38.94% of the patients (p ≤ 0.001) after approximately 6 months’ administration. Related to the patients with details on the severity of dysmenorrhoea at the two recording times, the number of patients with severe and moderate symptoms decreased from 22.19% to 0.49% and from 40.08% to 5.94% respectively in the course of the observational study. In line with the reduction of dysmenorrhoea, the use of analgesics also decreased. After approximately 6 months’ administration only 14.53% of the patients took analgesics due to symptoms compared with 57.28% at the start of the observational study. Accordingly the number of those patients requiring no analgesics increased from 42.72% to 85.47% (p ≤ 0.001). Dysmenorrhoea-related absenteeism also decreased. Whereas prior to Belara® administration 27.65% of the patients were occasionally absent from school or work and 1.34% during each menstrual period, the figures were only 2.26% and 0.08% respectively after approximately 6 months’ administration. The number of patients with no absenteeism increased accordingly from 71.01% to 97.66% (p ≤ 0.001).

There was also a distinct improvement of existing symptoms in other disorders. The number of patients with premenstrual syndrome decreased from 36.22% to 19.28%. Mood swings were documented on treatment with Belara® in 24.78% of the patients compared to 39.71% prior to starting treatment with Belara®. Breast tenderness decreased from 42.74% to 28.65%, headache from 35.27% to 22.38% and circulatory disturbances from 25.97% to 12.49%. Whilst prior to starting treatment with Belara® 66.89% of the patients suffered from greasy/acne-prone skin, after approximately 6 cycles this was only the case in 33.89% of the patients. The number of patients with greasy hair also decreased from 57.24% to 25.19%. Alopecia was documented prior to Belara® in 22.09% of the patients and after approximately 6 administration cycles only in 7.99%

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of the patients (for all changes: p ≤ 0.001).

At the final visit the patient and the physician should assess the efficacy of Belara® with regard to dysmenorrhoea, skin and hair condition, well-being and an overall assessment compared to the last contraceptive. The physicians assessed the improvement of dysmenorrhoea symptoms as very good for 65.42% of the patients (n = 4514), as good for 25.79%, as moderate for 1.97% and as poor for 0.38% (no details: 6.45%). Skin and hair condition were assessed as very good for 54.70% of the patients, as good for 36.18%, as moderate for 2.55% and as poor for 0.31% (no details: 6.27%). Well-being was assessed as very good for 58.00% of the patients, as good for 33.07%, as moderate for 2.39% and as poor for 0.47% (no details: 6.07%). For the 1887 patients who had already taken an oral contraceptive before Belara®, the physicians assessed Belara® compared to the last oral contraceptive as very good in 54.53% of the patients, as good in 33.07%, as moderate in 3.71% and as poor in 0.64% (no details: 8.06%). 63.38% of the users assessed the improvement of dysmenorrhoea symptoms as very good, 26.67% as good, 2.50% as moderate and 0.89% as poor (no details: 6.56%). Skin and hair condition were assessed as very good by 52.55% of the patients, as good by 35.98%, as moderate by 3.97% and as poor by 1.02% (no details: 6.49%). Well-being was assessed as very good for 55.18% of the patients, as good for 33.65%, as moderate for 3.54% and as poor for 1.37% (no details: 6.25%). Of the 1887 patients who had already taken an oral contraceptive before Belara®, Belara® was assessed as very good by 52.68% of the patients, as good by 33.33%, as moderate by 4.45% and as poor by 1.64% compared to the last contraceptive (no details: 7.90%).

Tolerability results A total of 223 patients reported 284 non-serious adverse drug reactions (ADRs, “side-effects”). There were no serious ADRs.

According to MedDRA® coding (version 10.0) of a total of 284 ADRs the majority (n=134) were in the organ class “Reproductive system and breast disorders". This can be explained by the fact that the 84 cases of metrorrhagia include spottings and breakthrough bleedings. With a further 35 reports of amenorrhoea (11 reports), dysmenorrhoea (8 reports), breast pain (10 reports) and breast problems (6 reports) it was the labelled side-effect spectrum of Belara®. In the organ class “Investigations” the side-effect weight increase labelled for Belara® can be exclusively found (n = 42). With n=28, n=23, n=22 and n=13 ADRs, there was another focus in the organ classes “Nervous system disorders”, “Gastrointestinal disorders”, “Skin and subcutaneous tissue disorders” and “Psychiatric disorders” respectively. Eighty-one of these 86 side-effects corresponded to the labelled

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side-effect spectrum of Belara® (including headache, dizziness, migraine, nausea, vomiting, lower abdominal problems, acne, alopecia, depression/mood swings). On consideration of all side-effects classified as labelled/declared the incidences (related to the safety population of 4824) corresponded to or were below those given in the reference documents on Belara® (except “change of appetite”: 0.15 versus

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and 2 mg CMA contained in Belara® proved to be very efficient for both contraception and the treatment of hormone-related problems. Administration of Belara® resulted in a distinct increase in cycle stability and a reduction in dysmenorrhoea disorders. For the first time data on the use of analgesics and absence from school/work due to dysmenorrhoea were documented. In both categories a distinct reduction was registered within the observation period. There was also an improvement in androgen-dependent disorders of dermal function and hair follicle, e.g. seborrhoea and alopecia.

Assessment of the benefit/risk profile: the results of this study give no indication to change the current assessment of the benefit/risk profile of Belara®.

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2 INTRODUCTION

2.1 Background Belara®, a monophasic micropill with 21 tablets, contains 30 µg ethinylestradiol (EE) and 2 mg chlormadinone acetate (CMA) per film-coated tablet. The special feature of Belara® is the combination of a low estrogen dose of 30 µg EE with a progestogen (CMA), derived directly from a progesterone. Extensive clinical studies on Belara®’s efficacy and tolerability also show the excellent efficacy of CMA on androgen-related dermal changes such as acne and seborrhoea.

2.2 Aim of the Evaluation Earlier observational studies (Schramm and Steffens 2002 and 2003, Schramm and Heckes 2007) with Belara® showed that in women who switched from another contraceptive to Belara® existing dysmenorrhoea improved significantly or disappeared. The same also applied for other symptoms, e.g. headache or breast tenderness.

The aim of this observational (non-interventional) study was to follow up the significance and changes in dysmenorrhoea and other symptoms in daily practice on administration of Belara® to a large group of women, thus extending the database regarding these effects. For the first time data on the use of analgesics and absence from school/work due to dysmenorrhoea were documented.

Furthermore the data collected in this observational study were also intended to broaden the database with regard to tolerability and recording of adverse drug reactions. This observational study is also an instrument for fulfilling the product surveillance obligation imposed by legislation, by collecting and evaluating information about Belara® as actually used in medical practice.

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3 METHOD

3.1 Study Procedure Data acquisition of this observational study was prospective. At the start of the observational study as well as recording demographic and morphometric data (age, height, weight and occupation) information on blood pressure and pulse was also recorded. For restarters after pregnancy/breast-feeding additional information on date of birth and duration of lactation was given. Existing risk factors for the administration of hormonal preparations were also recorded from both the patient’s case history and her family case history. The administration of preparations for previous contraception and details of the reasons for starting treatment with Belara® or switching to Belara® were also documented. In addition to the course of the cycle, the extent of dysmenorrhoea and other symptoms was recorded before starting treatment with Belara® and after approximately 6 cycles/6 blisters. The following parameters were recorded:

• regularity of menstruation and bleeding intensity;

• intensity and frequency of period pain;

• premenstrual syndrome, mood swings, breast tenderness, headache, skin and hair condition.

The end of individual therapy with Belara® during the documentation period was recorded with details of the last administration cycle and the reason for discontinuation. Adverse drug reactions were recorded using a separate safety reporting form. If the individual duration of administration was 6 cycles/6 blisters, the date of the final visit, details of weight, blood pressure, pulse and regularity of administration were documented. Both the physician and the patient should give an overall assessment of Belara® whereby particularly the temporal course of dysmenorrhoea, changes in skin and hair condition and general well-being were documented.

3.2 Medication Belara®, a monophasic micropill containing 30 µg ethinylestradiol (EE) and 2 mg chlormadinone acetate (CMA) per tablet, has been approved in Germany since 1998. The administration of Belara® per pill cycle was once daily for 21 days followed by a seven-day pill-free interval (conventional cycle regimen). It was also possible to take Belara® in an extended cycle regimen (administration of 2-6 blisters consecutively followed by a seven-day pill-free interval).

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3.3 Efficacy and Tolerability Parameters The following efficacy parameters were recorded: Non-contraceptive efficacy parameters (additional benefits):

• regularity of menstruation and bleeding intensity; • intensity and frequency of period pain; • premenstrual syndrome, mood swings, breast tenderness, headache, skin and hair condition. • final assessment by physician and patient regarding reduction of skin problems and

dysmenorrhoea, well-being and assessment of Belara® compared to the previous contraceptive

Contraceptive efficacy parameters: • contraceptive efficacy (Pearl Index)

The following tolerability parameters were recorded: • occurrence of adverse drug reactions

3.4 Data Entry and Data Management The data were recorded according to the variables and units in the case report form using the data management programme DMSys® version 5.0. Plausibility checks were carried out (simultaneously and sequentially).

Duplicate data recording To enable safe identification of patients the following variables were recorded in duplicate:

• Form No.: • Patient No. • Initials

Data validation To improve the quality of the data the following validation methods were used: Dates Dates relating to each other (e.g. baseline visit versus final visit) were checked for consistency (logically the date of a final visit could not be before the date of a baseline visit). Dates with scheduled chronology were also checked for consistency (e.g. the termination date of the last administered contraceptive must be before the beginning of treatment with Belara®). Inconsistent data were compared with the details in the original case report form and if necessary corrected. If this was inconclusive, the date was not taken into account in the analysis.

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Simultaneous plausibility checks Obviously implausible details, e.g. diastolic BP higher than systolic BP or assessment scores outside the valid range, were queried during the data recording and corrected accordingly. Extreme value check/Check of categories with a low number of entries All extreme values (minima and maxima) and low number of category parameter values on the following variables were checked in the original s and using the entries found here were validated: age, height, weight, body mass index (BMI), baby’s date of birth, date of stopping breast-feeding, start and end of the last administration of an oral contraceptive before Belara®, date of baseline visit, start of Belara® administration, administration of analgesics: number of tablets taken per menstruation and number of days with administration of analgesics, blood pressure, pulse.

Consistency check of mutually dependent details In addition to the dates all mutually dependent details were also subject to consistency checks. The checks concerned particularly the correlation between “yes/no” details (e.g. thrombo-embolic diseases in the family) and respective free-text details and/or further specifications. In the case of inconsistent entries the free-text details took priority (exception: the free-text details concerned a general comment which was not associated with the actual question).

Risk factors A patient was considered to be overweight if from the documented height and body weight a BMI ≥25 kg/m2 resulted or if in the section "Risk factors for the administration of oral contraceptives" of the CRF "overweight", "obesity" etc. was noted. Nicotine abuse was present if “Smoker” was marked “Yes” or if “Nicotine abuse”, “Smoker” etc. was noted in the section “Risk factors for the administration of oral contraceptives" of the CRF.

Oral contraception in the case history In the CRF it was asked whether oral contraceptives (OC) had been taken before Belara®. In the case of previous administration the time period of the last administration and last preparation should be stated. The details regarding oral contraception "yes/no" and last administered OC were not always consistent or clear. For example, the question about oral contraceptives was affirmed, but a non-oral contraceptive (NOC) or a NOC and an oral contraceptive stated as the preparation. Therefore, the following definitions were made for establishing the last contraceptive method before Belara®.

• Oral contraception as the last contraceptive method: exclusively oral contraceptives stated as contraception in the case history.

• Initial treatment with oral contraceptives: no history of oral contraceptives and no details in the free-text field “Preparation”.

• Other contraception as the last contraceptive method: details of non-oral contraceptive (NOC) only

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Course findings Corresponding to the surveillance protocol for the analysis of the cycle course, dysmenorrhoea and other symptoms in the course of treatment only patients were considered who took Belara® for at least 6 cycles or 6 blisters.

Dysmenorrhoea In some cases patients denied suffering from dysmenorrhoea but at the same time gave details on the intensity of the symptoms, administration of analgesics based on these symptoms and taking time off school/work due to these symptoms. In this case the procedure was as follows.

If the lowest rating was stated at most in all three dependent variables (intensity of symptoms: very mild; administration of analgesics: never; absenteeism: never), these details were not taken into account and it was assumed that there had been no dysmenorrhoea. If in at least one of the three variables a higher rating was stated, then “Symptoms during menstruation” was changed from “No” to “Yes”.

3.5 Statistical Evaluation Adequate data management procedures together with descriptive and explorative statistical procedures were used for the evaluation.

Absolute and relative frequencies, mean, standard deviation, first percentile, 25th percentile, median, 75th percentile and 99th percentile were calculated depending on the scale. Each table showed to which random sample the calculations referred. If the tables contain the information "relative frequencies adjusted", the percentages were adjusted without considering patients with missing details. Although the curve variables cycle course, dysmenorrhoea and other symptoms are merely depicted on an ordinal scale, means and standard deviations were calculated to at least roughly quantify the overall change of the symptoms.

For the curve variables (cycle course, dysmenorrhoea, other disorders and vital parameters) descriptive p values were calculated for the changes in the course of the observational study using Wilcoxon rank tests or McNemar’s test.

Unless otherwise explicitly stated in the tables all calculations were carried out using the computer statistics programme SPSS for Windows (release 11.0.1). Each table showed to which random sample the calculations referred. Possible discrepancies in the reference random sample are due to missing data. PHARMSOFT Dr. B. Rodust GmbH, Ascheberg evaluated the adverse drug reactions. Factum GmbH, Offenbach evaluated all other parameters. If percentages in the tables and graphs, in which multiple classifications are not possible, do not add up exactly to 100%, this is due to inaccuracy in rounding off figures.

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3.6 Calculation of the Pearl Index Total treatment time The calculation of the total treatment time for patients without premature termination of treatment was based on a consumption of 6 blisters (6x21 days) plus in each case a 7-day pill-free interval after each administration cycle (i.e. for normal administration cycle 6x7 days, for an extended cycle with a pill-free interval after 2 blisters 3x7 days, etc.). The total treatment time was based on the blisters consumed so far plus the intervals in administration of completed administration cycles in the case of premature termination, i.e. in the case of termination after 3 cycles or 3 blisters the treatment duration for normal mode of administration was 3x(21+7)= 84 days and for extended cycle with a pill-free interval after 2 blisters was 1x(42+7)= 70 days. If there were no details as to whether or when the treatment was terminated, a treatment duration of one cycle (28 days) was assumed for the patients with normal mode of administration and for all other patients (extended cycle or no details on mode of administration) a treatment duration of 21 days (1 blister) was assumed. Details on the total number of cycles are given for the safety population (for calculation of the Pearl Index of the safety population), for the efficacy total population and for the efficacy subgroup (1): patients up to 24 years and the efficacy subgroup (2): patients up to 19 years (for the calculation of the Pearl indices of the 2 efficacy subgroups).

Pearl Index The following formulae were used for calculating the Pearl Index (PI):

• Related to the patients with normal administration cycle:

cyclesday -28 ofnumber Total100xcycles13xspregnancie ofNumber PI =

• Related to the patients with normal administration cycle and extended cycle:

Basis cycle days

(days) cycles extended of no. total (days) cyclestion administra normal of no. Total100 x days 365 x spregnancie ofNumber PI

+=

Basis equivalent number of cycles

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cycles of no. equivalentin cycles extended of no. total cycles admin. normal of no. Total100 x cycles 13 x spregnancie ofNumber PI

+=

whereby the following applies:

Normal cycle = 28 days = equivalent to 1 cycle Extended cycle with 2 blisters = 49 days = equivalent to 1.75 cycles Extended cycle with 3 blisters = 70 days = equivalent to 2.5 cycles Extended cycle with 4 blisters = 91 days = equivalent to 3.25 cycles Extended cycle with 5 blisters = 112 days = equivalent to 4 cycles Extended cycle with 6 blisters = 133 days = equivalent to 4.75 cycles

3.7 Analysed Random Samples As planned in the surveillance protocol, 4514 patients were documented prospectively (efficacy total population). Retrospective documentation was available for 310 patients as the start of treatment with Belara® was before the date of the baseline visit and before the start of the observational study (1.8.2003). Therefore, there was data for a total of 4824 patients (safety population).

The following analyses were carried out for both populations (efficacy total population and safety population):

• morphometric data; • mode of administration: conventional/extended cycle; • continuation or termination of treatment with Belara®.

The data of the efficacy total population are mainly presented in the report. The tables contain the analyses of both populations. The following analyses were carried out for the efficacy total population (n = 4514):

• general case history; • starting/switching to Belara®; • continuation/premature termination of treatment with Belara®; • changes of dysmenorrhoea and other disorders in the course of treatment; • final assessment of Belara®.

For the safety population (n = 4824) the following were carried out:

• analysis of the ADRs; • calculation of the PI.

The following subgroups were formed from the efficacy total population (n = 4514) the results of which are given in the tables:

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• Starters: all patients who with the current Belara® medication received an oral contraceptive

for the first time or for whom the interval between the current Belara® medication and a previous oral contraceptive was at least 3 months (n = 2914).

• Switchers: all patients who prior to the current Belara® medication had already taken an oral contraceptive and there was either no interval between Belara® and the previous oral contraceptive or the interval was only a maximum of 2 months (n = 1170).

For the group “Switchers” the following subgroups were formed:

• switch from combined oral contraceptives (COCs) with 2nd generation progestogens to Belara® (n = 524)

• switch from COCs with 3rd generation progestogens to Belara® (n = 225) • switch from COC with dienogest to Belara® (n = 121) • switch from COC with drospirenone to Belara® (n = 73) • switch from monophasic COCs with 30 µg ethinylestradiol (EE) to Belara®

(n = 518) • switch from monophasic COCs with 20 µg EE to Belara® (n = 255) • switch from multiphasic COCs to Belara® (n = 142) • switch from levonorgestrel and estrogen (20 µg) to Belara® (n = 170)

• Classification according to age group:

Up to 14 years (n = 164)

15 – 19 years (n = 1853) 20 – 24 years (n = 1065)

25 – 29 years (n = 551) 30 – 34 years (n = 452)

35 – 39 years (n = 256) 40 years and older (n = 128)

• Patients with normal mode of administration (21 tablets + 7-day pill-free interval;

n = 4263) • Patients with a different mode of administration (extended cycle; n = 180) • Restarters (n = 258) • Classification according to weight group:

Underweight (BMI < 18.5 kg/m²; N = 345) Normal weight (BMI 18.5 bis < 25.0 kg/m²; N = 3310)

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Overweight (BMI ≥ 25.0 kg/m²; N = 712) The following subgroups were subsequently evaluated from the efficacy total population (n = 4514): Efficacy subgroup (1): ≤ 24 years, n = 2886

Efficacy subgroup (2): ≤ 24 years with dysmenorrhoea, n = 2376 Efficacy subgroup (3): ≤ 19 years, n = 1923

Efficacy subgroup (4): ≤ 19 years with dysmenorrhoea, n = 1644 Data on the Pearl Index and tolerability are in the report. All other results are in the tables.

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4 RESULTS ON THE EFFICACY OF BELARA®

4.1 General Study Outcome As planned in the surveillance protocol, 4514 patients were documented prospectively (efficacy total population). Most of the following evaluations refer to this patient sample. Nevertheless for individual evaluations (side-effects, pregnancies) the retrospectively documented patients were also included (details see 3.7). Efficacy total population plus retrospectively documented patients form the safety population (n = 4824). The safety population was used for calculating the centres involved. The data of 4824 patients from 608 centres (median: 8 patients per centre) were recorded from August 2003 (start of the observational study) to November 2004 (last documented examination).

4.2 General Patient Data

4.2.1 Morphometric Data The median age in the efficacy total population (prospectively documented patients, n = 4514) was 20.86 years. 3.63% of the patients were ≤ 14 years old, 41.05% were between 15 and 19 years old, 23.59% were between 20 and 24 years old and 30.73% were ≥ 25 years old. Details of age were missing in 1.00%. The youngest patient was 13 years old and the oldest 51 years old.

Table 4.2.1:1 Age of the patients (categorial) (Efficacy Total Population)

n % ≤ 14 years 164 3.63%15 - 19 years 1853 41.05%20 - 24 years 1065 23.59%25 - 29 years 551 12.21%30 - 34 years 452 10.01%35 - 39 years 256 5.67%≥ 40 years 128 2.84%No details 45 1.00% Total 4514 100.00%

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The median height of the patients was 168.00 cm. The median body weight was 61.00 kg. The median body mass index (BMI) was 21.87 kg/m2. 7.90% of the patients for whom calculation of the BMI was possible, were underweight, 75.80% normal weight and 16.30% overweight.

Table 4.2.1:2 Weight (categorial) Subgroup: patients with corresponding details (Efficacy Total Population)

n % Underweight 345 7.90%Normal weight 3310 75.80%Overweight 712 16.30% Total 4367 100.00%Classification according to WHO, 2000: Underweight: BMI < 18.5 kg/m2 Normal weight: BMI 18.5 - < 25 kg/m2 Overweight: BMI from 25 kg/m2

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4.2.2 Patient’s Occupation A total of 56.96% of the patients were school pupils, students or were in professional training; 30.88% were employed; 10.61% were housewives. Another occupation was stated for 0.91% and for 0.64% there were no details on occupation.

Table 4.2.2:1 Occupation (Efficacy Total Population)

n % School pupil 1566 34.69%Student 516 11.43%Employed 1394 30.88%Trainee 489 10.83%Housewife 479 10.61%Other 41 .91%No details 29 .64% Total 4514 100.00%

4.2.3 Restarters A total of 5.72% of the patients were restarters after pregnancy/breast-feeding (n = 258). Oral contraception was started again in a median of 6.24 months after the baby's birth. 68.99% of the patients had breast-fed, 30.62% had not breast-fed and for one patient (0.39%) there were no relevant details. Oral contraception was desired again in a median of 2.00 months after stopping breast-feeding (see table 2.1.3.2).

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4.2.4 General Case History

4.2.4.1 Risk Factors 32.74% of the patients were smokers and 15.77% of the patients were overweight. 1.91% of the patients had known thrombo-embolic diseases in the family and 1.17% reported other risk factors (see table 2.2.1.3). Table 4.2.4.1:1 Risk factors (Efficacy Total Population)

n % Nicotine abuse 1478 32.74% Abnormal thrombo-embolic diseases in the family 86 1.91% Overweight* 712 15.77% Other risk factors for OC administration ** 53 1.17% Total 4514 100.00% * BMI greater than 25 kg/m2 or 'Overweight' ** Most common single classifications: varicosis, hypertension, diabetes, migraine

4.2.4.2 Previous Contraception A total of 52.99% of the patients received an oral contraceptive for the first time. In 41.80% of the patients oral contraception was stated as the last contraceptive method before taking the current Belara® medication. 0.47% of the patients chose another contraceptive method before Belara® and in 4.74% there were no details available. Table 4.2.4.2:1 Last contraceptive method (Efficacy Total Population)

n % Last contraceptive method: OC 1887 41.80%Initial treatment with OC 2392 52.99%Last contraceptive method: other* 21 .47%No details 214 4.74% Total 4514 100.00%* IUP, vaginal ring, depot, coil, patch 64.55% of the patients were started on Belara® and 25.92% were switched to Belara®. In 9.53% of the patients a classification was not possible (8.15% of the patients could not be classified due to the definition of starter and switcher and there were no details for 1.79%).

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Table 4.2.4.2:2 Starter/Switcher (Efficacy Total population)

n % Starter 2914 64.55%Switcher 1170 25.92%No details 430 9.53% Total 4514 100.00%

44.79% of the patients who switched to Belara® (n = 1170) had previously taken an oral contraceptive with a second generation progestogen. 19.23% had taken a third generation progestogen and 10.34% dienogest.

Table 4.2.4.2:3 Classification according to progestogens Preparation previously taken Subgroup: switcher (Efficacy Total Population)

n % First generation (norethisterone, norethisterone acetate, lynestrol)/EE

30 2.56%

Second generation (levonorgestrel)/EE 524 44.79% Third generation (desogestrel, gestodene, norgestimate)/EE 225 19.23% CMA/EE 57 4.87% CPA/EE 64 5.47% Dienogest/EE 121 10.34% Drospirenone/EE 73 6.24% Minipill 32 2.74% Previous COC – progestogen component unknown 44 3.76% Total 1170 100.00%

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Before switching to Belara® most patients took monophasic oral contraceptives with a daily dose of 30 µg ethinylestradiol (EE) (44.27%). 21.79% of the patients took monophasic oral contraceptives with 20 µg ethinylestradiol and 4.02% of the patients took COCs with 50 µg EE. 12.14% of the patients took multiphasic oral contraceptives.

Table 4.2.4.2:4 Classification according to preparation composition Preparation previously taken Subgroup: switcher (Efficacy Total Population)

n % Monophasic, no details on EE dose 46 3.93%Monophasic, EE dose: 20 µg 255 21.79%Monophasic, EE dose: 30 µg 518 44.27%Monophasic, EE dose 35 µg 112 9.57%Monophasic, EE dose: 50 µg 47 4.02%Multiphasic 142 12.14%No details possible 50 4.27% Total 1170 100.00%

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4.3 Treatment with Belara®

4.3.1 Reason for Starting/Switching Dysmenorrhoea and contraception were the most frequent reasons for starting Belara® treatment (66.35% and 62.01% of all prospectively documented patients, respectively). In 47.63% of the patients skin/hair problems were reported, in 20.12% cycle irregularities and in 8.15% other reasons (multiple classifications possible). The reason for treatment in the subgroups starters and switchers was dysmenorrhoea, skin/hair problems and cycle irregularities. The incidence was virtually the same. Contraception was stated as the reason for treatment distinctly more frequently in the starters than in the switchers (75.09% vs. 34.62%).

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Table 4.3.1:1 Reason for starting/switching (Multiple classifications possible) (Efficacy Total Population)

Starting Switching No details Total N % n % n % n %

Contraception 2188 75.09% 405 34.62% 206 47.91% 2799 62.01%Dysmenorrhoea 1997 68.53% 772 65.98% 226 52.56% 2995 66.35%Skin/hair problems 1348 46.26% 597 51.03% 205 47.67% 2150 47.63%Cycle irregularity 569 19.53% 249 21.28% 90 20.93% 908 20.12%Other 111 3.81% 204 17.44% 53 12.33% 368 8.15%No details 56 1.92% 9 .77% 16 3.72% 81 1.79% Total 2914 100.00% 1170 100.00% 430 100.00% 4514 100.00%

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4.3.2 Mode of Administration Usually tablets were administered for 21 days followed by a seven-day pill-free interval (normal mode of administration, 94.44% of the patients). Contrary to this 3.99% of the patients took Belara® in the extended cycle regimen. The most frequent was with a pill-free interval after 3 blisters (56.67% of the patients with extended cycle as mode of administration). There were no details for 1.57% of the patients.

Table 4.3.2:1 Mode of administration of Belara® (Efficacy Total Population)

n % Normal (21 tablets + 7-day pill-free interval) 4263 94.44%Different mode of administration (extended cycle)

180 3.99%

No details 71 1.57% Total 4514 100.00%

Table 4.3.2:2 Different mode of administration (extended cycle): time of pill-free interval Subgroup: patients with a different mode of administration (Efficacy Total Population)

n % No pill-free interval 2 1.11%After 2 blisters 20 11.11%After 3 blisters 102 56.67%After 4 blisters 12 6.67%After 5 blisters 0 .00%After 6 blisters 13 7.22%No details 31 17.22% Total 180 100.00%

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4.3.3 Regularity of Administration 82.30% of the patients took Belara® regularly during the approx. 6-month observation period. Belara® was not taken regularly in 7.78% of the patients and there were no details for 9.92% of the patients.

Table 4.3.3:1 Regularity of administration (Efficacy Total Population)

n % Yes 3715 82.30%No 351 7.78%No details 448 9.92% Total 4514 100.00% In patients with irregular administration of Belara® there was mostly one single omission of administration per cycle (68.66%). Administration was forgotten several times per cycle in 27.35% (see table on the next page).

Regularity of administration increased dependent on age. It was 75.00% for patients up to 14 years and for patients ≥ 40 years it was 86.72% (see table 3.3 of table appendix).

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Table 4.3.3:2 Regularity of administration (Efficacy Total Population)

Forgotten once Forgotten several times

No details Total

n % n % n % n % No details on the number of cycles 24 6.84% 16 4.56% 11 3.13% 51 14.53%Forgotten in 1 cycle 124 35.33% 15 4.27% 3 .85% 142 40.46%Forgotten in 2 cycles 76 21.65% 44 12.54% 0 .00% 120 34.19%Forgotten in 3 cycles 13 3.70% 13 3.70% 0 .00% 26 7.41%Forgotten in 4 cycles 0 .00% 0 .00% 0 .00% 0 .00%Forgotten in 5 cycles 0 .00% 1 .28% 0 .00% 1 .28%Forgotten in 6 cycles 4 1.14% 7 1.99% 0 .00% 11 3.13% Total 241 68.66% 96 27.35% 14 3.99% 351 100.00%

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4.3.4 Continuation or Termination of Belara® Treatment After 6 Cycles In 86.26% of the patients treatment with Belara® was continued beyond the observation period of 6 cycles or 6 blisters, in 12.30% of the patients administration was terminated at the latest after 6 cycles or 6 blisters. The most frequent reasons for premature termination were persistent symptoms/intolerance (52.61% of the patients), patient no longer attended (14.95%) and contraception no longer desired (14.05%).

Table 4.3.4:1 Continuation of administration of Belara® beyond the observation period of 6 cycles or 6 blisters (Efficacy Total Population)

n % Continued 3894 86.26%Discontinued 555 12.30%No details 65 1.44% Total 4514 100.00%

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Table 4.3.4:2 Reason for terminating treatment with Belara® Subgroup: patients, who discontinued treatment with Belara® (Efficacy Total Population)

n % Contraception no longer desired 78 14.05% Pregnancy 6 1.08% Existing risk factors 5 .90% Switch to other OC 13 2.34% Switch to other contraceptive method 14 2.52% Patient no longer attended 83 14.95% Financial reasons 24 4.32% Patient’s request 10 1.80% Other reasons 18 3.24% Persisting symptoms/intolerance* 292 52.61% No details 38 6.85% Total 555 100.00% * Most common single classifications: cycle disorders (n = 116), weight problems (n = 51), skin/hair problems (n = 49), dysmenorrhoea (n = 33), headache (n = 23), gastrointestinal intolerance (n = 21), breast tenderness/enlargement (n = 18)

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Premature Termination of Administration of Belara® 6.60% of the patients terminated Belara® administration before the planned observation period of 6 cycles or 6 blisters (premature termination). The most frequent reason stated for premature termination of treatment was persisting symptoms/intolerance (66.78% of the patients terminated Belara® administration prematurely).

Table 4.3.4:3 Was the administration of Belara® terminated prematurely? (Efficacy Total Population)

n % Yes 298 6.60%No 4048 89.68%No details 168 3.72% Total 4514 100.00%

Table 4.3.4:4 Reason for premature termination of treatment with Belara® Subgroup: patients, who terminated treatment with Belara® prematurely (Efficacy Total Population)

n % Contraception no longer desired 44 14.77% Pregnancy 6 2.01% Existing risk factors 2 .67% Switch to other OC 10 3.36% Switch to other contraceptive method 3 1.01% Patient no longer attended 17 5.70% Financial reasons 11 3.69% Patient’s request 5 1.68% Other reasons 14 4.70% Persisting symptoms/intolerance* 199 66.78% No details 7 2.35% Total 298 100.00% * Most common single classifications: cycle disorders (n = 81), weight problems (n = 36), skin/hair problems (n = 34), gastrointestinal intolerance (n = 20), headache (n = 19), dysmenorrhoea (n = 18), breast tenderness/enlargement (n = 14)

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4.4 Course Findings

4.4.1 Duration of Observation The median observation period was 6.01 months.

Table 4.4.1:1 Observation period (months)* (Efficacy Total Population)

Mean

SD

1st perc.

25th perc.

Median

75th perc.

99th perc.

n

Observation period 6.10 1.15 3.09 5.49 6.01 6.60 9.63 4044* Final visit in relation to the first Belara® administration

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4.4.2 Evaluation Population Corresponding to the surveillance protocol for the analysis of the cycle course, dysmenorrhoea and other symptoms in the course of treatment only patients were considered who took Belara® for at least 6 cycles or 6 blisters.

Moreover, the following tables are limited to patients with valid details at both visits (before administration of Belara® and after approx. 6 administration cycles or 6 blisters).

4.4.3 Cycle Course

4.4.3.1 Cycle Stability The number of those patients with a regular cycle distinctly increased on administration of Belara®. After approximately 6 months’ administration the number of patients with a regular cycle increased from 66.70% to 98.09%, whilst the number of patients with an irregular cycle decreased from 33.30% to 1.91% (p ≤ 0.001).

Table 4.4.3:1 Cycle course: cycle stability Subgroup: patients with baseline and final visit (Efficacy Total Population)

Regular Irregular Total N % n % n %

Before Belara®* 2580 66.70% 1288 33.30% 3868 100.00%Final visit** 3794 98.09% 74 1.91% 3868 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

The cycle stabilising effect of Belara® was also to be observed in patients, who had already taken oral contraceptives before Belara® ("switchers"). The number of patients with a regular cycle in the course of treatment with Belara® increased from 79.18% to 97.28%.

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Table 4.4.3:2 Cycle course: cycle stability depending on starting/switching Subgroup: patients with baseline and final visit (Efficacy Total Population) Starters


Before Belara®* 1554 61.28% 982 38.72% 2536 100.00%Final visit** 2499 98.54% 37 1.46% 2536 100.00% Switchers


Before Belara®* 787 79.18% 207 20.82% 994 100.00%Final visit** 967 97.28% 27 2.72% 994 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters

4.4.3.2 Intensity of Withdrawal Bleeding Whilst prior to starting treatment with Belara® 26.01% of the patients had severe to very severe menstrual bleeding, in the final visit this was only the case in 0.94% of the patients. In the course of the observational study the number of patients with slight to moderate menstruation increased from 73.99% to 99.06% (p ≤ 0.001).

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Table 4.4.3.2:1 Cycle course: intensity of withdrawal bleeding (categorial) Subgroup: patients with baseline and final visit (Efficacy Total Population)

Slight Moderate Severe Very severe Total n % n % n % n % n %

Before Belara®* 579 15.11% 2257 58.88% 890 23.22% 107 2.79% 3833 100.00%

Final visit** 1788 46.65% 2009 52.41% 33 .86% 3 .08% 3833 100.00%

* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

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4.4.3.3 Absence of Menstruation Absence of single periods was less frequently observed whilst taking Belara® than before administration. Whilst prior to starting treatment with Belara® this was the case in 22.09% of the patients, in the final visit this was documented only in 6.92% (p ≤ 0.001). Frequent to very frequent absence of menstruation was stated in the final visit only in 0.50% of the patients compared to 5.77% prior to Belara® administration.

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Table 4.4.3.3:1 Cycle course: absence of menstruation Subgroup: patients with baseline and final visit (Efficacy Total Population)

No Rare Frequent Very frequent Total n % N % n % n % n %

Before Belara®* 2983 77.91% 625 16.32% 188 4.91% 33 .86% 3829 100.00%Final visit** 3564 93.08% 246 6.42% 12 .31% 7 .18% 3829 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

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4.4.3.4 Intermenstrual Bleeding On administration of Belara® there were fewer cases of intermenstrual bleeding in the course of the observational study. Whilst prior to starting treatment with Belara® intermenstrual bleeding occurred in 32.02% of the patients, in the final visit this was the case only in 15.21% (p ≤ 0.001).

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Table 4.4.3.4:1 Cycle course: intermenstrual bleeding Subgroup: patients with baseline and final visit (Efficacy Total Population)

No Rare Frequent Very frequent Total n % N % n % n % n %

Before Belara®* 2615 67.98% 849 22.07% 343 8.92% 40 1.04% 3847 100.00%Final visit** 3262 84.79% 516 13.41% 62 1.61% 7 .18% 3847 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

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4.4.4 Dysmenorrhoea In the course of the observational study there was a distinct reduction in the intensity and incidence of dysmenorrhoea. Whilst prior to starting treatment with Belara® 78.56% of the patients suffered from dysmenorrhoea, this was only the case in 38.94% of the patients (p ≤ 0.001) after approximately 6 months’ administration.

Table 4.4.4:1 Dysmenorrhoea: symptoms during menstruation Subgroup: patients with baseline and final visit (Efficacy Total Population)

Symptoms No symptoms Total n % n % n %

Before Belara®* 3089 78.56% 843 21.44% 3932 100.00%Final visit** 1531 38.94% 2401 61.06% 3932 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; McNemar’s test

Related to the patients with details on the severity of dysmenorrhoea at the two recording times, the number of patients with severe and moderate symptoms decreased from 22.19% to 0.49% and from 40.08% to 5.94% respectively in the course of the observational study (moderate symptoms; see table on next page).

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Table 4.4.4:2 Dysmenorhoea: intensity of these symptoms Subgroup: patients with baseline and final visit (Efficacy Total Population)

No symptoms Very slight Slight Moderate Severe Total n % n % n % n % n % n %

Before Belara®* 839 21.75% 103 2.67% 513 13.30% 1546 40.08% 856 22.19% 3857 100.00%Final visit** 2378 61.65% 324 8.40% 907 23.52% 229 5.94% 19 .49% 3857 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

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Even in patients who had already taken oral contraceptives before Belara® ("switchers") there was a reduction in the incidence of symptoms from 75.30% before Belara® to 38.65% in the final visit.

Table 4.4.4:3 Dysmenorrhoea: symptoms during menstruation depending on starting/switching Subgroup: patients with baseline and final visit (Efficacy Total Population) Starters

Symptoms No symptoms Total N % n % n %

Before Belara®* 2097 81.15% 487 18.85% 2584 100.00%Final visit** 1023 39.59% 1561 60.41% 2584 100.00% Switchers

Symptoms No symptoms Total N % n % n %

Before Belara®* 756 75.30% 248 24.70% 1004 100.00%Final visit** 388 38.65% 616 61.35% 1004 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters

4.4.4.1 Administration of Analgesics Due To Symptoms In line with the reduction of dysmenorrhoea, the use of analgesics also decreased. After approximately 6 months’ treatment only 14.53% of the patients took analgesics due to symptoms compared with 57.28% at the start of the observational study. Accordingly the number of those patients requiring no analgesics increased from 42.72% to 85.47% (p ≤ 0.001). There was also a reduction of the frequency of analgesics taken and of the analgesic total dose per menstruation in patients who continued to take analgesics (see table 4.3.3).

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Table 4.4.4.1:1 Dysmenorrhoea: adminstration of analgesics Subgroup: patients with baseline and final visit (Efficacy Total Population)

Never Occasionally Frequently Every menstruation Total n % n % N % n % n %

Before Belara®* 1649 42.72% 1309 33.91% 541 14.02% 361 9.35% 3860 100.00%Final visit** 3299 85.47% 522 13.52% 21 .54% 18 .47% 3860 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p < 0.001; Wilcoxon signed-rank test

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4.4.4.2 Absence From School or Work Due To These Symptoms Dysmenorrhoea-related absenteeism decreased in the course of the observational study. Whereas prior to Belara® administration 27.65% of the patients were occasionally absent from school or work and 1.34% during each menstrual period, the figures were only 2.26% and 0.08% respectively after approximately 6 months’ administration. The number of patients with no absenteeism increased accordingly from 71.01% to 97.66% (p ≤ 0.001).

Table 4.4.4.2:1 Dysmenorrhoea: absence from school/work due to these symptoms Subgroup: patients with baseline and final visit (Efficacy Total Population)

Never Occasionally Every menstruation Total n % n % n % n %

Before Belara®*

2643 71.01% 1029 27.65% 50 1.34% 3722 100.00%

Final visit** 3635 97.66% 84 2.26% 3 .08% 3722 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

4.4.5 Other Disorders

4.4.5.1 Premenstrual Syndrome 80.72% of the patients no longer had any premenstrual problems on treatment with Belara®, compared to 63.78% before starting administration of Belara®. The number of patients with slight PMS decreased from 23.22% to 17.98%, those with moderate problems from 10.45% to 1.23% and those with severe problems from 2.55% to 0.08% (p ≤ 0.001).

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Table 4.4.5.1:1 Other disorders: PMS Subgroup: patients with baseline and final visit (Efficacy Total Population)

No Slight Moderate Severe Total n % N % n % n % n %


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4.4.5.2 Mood Swings 75.22% of the patients had no mood swings on treatment with Belara® compared to 60.29% before starting administration of Belara®. The number of patients with slight mood swings decreased from 27.45% to 22.53%, those with moderate mood swings from 9.79% to 2.14% and those with severe mood swings from 2.47% to 0.10% (p ≤ 0.001).

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Table 4.4.5.2:1 Other disorders: mood swings Subgroup: patients with baseline and final visit (Efficacy Total Population)



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4.4.5.3 Breast Tenderness 71.35% of the patients had no feeling of tension in the breasts on treatment with Belara®, compared to 57.26% before starting administration of Belara®. The number of patients with slight tenderness of the breasts decreased from 29.80% to 24.97%, those with moderate tenderness from 10.76% to 3.41% and those with severe tenderness from 2.19% to 0.28% (p ≤ 0.001).

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Table 4.4.5.3:1 Other disorders: breast tenderness Subgroup: patients with baseline and final visit (Efficacy Total Population)



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4.4.5.4 Headache 77.62% of the patients had no headaches on treatment with Belara® compared to 64.73% before starting administration of Belara®. The number of patients with slight headache decreased from 23.78% to 19.83%, those with moderate headache from 8.87% to 2.14% and those with severe headache from 2.62% to 0.41% (p ≤ 0.001).

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Table 4.4.5.4:1 Other disorders: headache Subgroup: patients with baseline and final visit (Efficacy Total Population)



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4.4.5.5 Circulatory disturbances 87.51% of the patients had no circulatory disturbances on treatment with Belara® compared to 74.03% before starting administration of Belara®. The number of patients with slight circulatory disturbances decreased from 17.36% to 11.52%, those with moderate circulatory disturbances from 6.97% to 0.89% and those with severe circulatory disturbances from 1.63% to 0.08% (p ≤ 0.001).

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Table 4.4.5.5:1 Other disorders: circulatory disturbances Subgroup: patients with baseline and final visit (Efficacy Total Population)


Before Belara®* 2899 74.03% 680 17.36% 273 6.97% 64 1.63% 3916 100.00%Final visit** 3427 87.51% 451 11.52% 35 .89% 3 .08% 3916 100.00%* the last 3 months ** after 6 cycles or 6 Belara® blisters Change after approx. 6 cycles or 6 blisters vs. baseline: p ≤ 0.001; Wilcoxon signed-rank test

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4.4.5.6 Greasy/acne-prone Skin 66.11% of the patients did not have greasy/acne-prone skin on treatment with Belara®, compared to 33

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