One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethisterone acetate in postmenopausal women

Maturitas 57 (2007) 171–181

One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethisterone acetate in postmenopausal women G¨oran Samsioe a,∗ , Vladimir Dvorak b , Andrea R. Genazzani c , Bernd Hamann d , Jorma Heikkinen e , Alfred O. Mueck f , Jacek Suzin g , Fernando T. Kawakami h , Alberto Ferreira h , Dongming Sun h , Miguel Arguinzoniz h a

c

Department of Obstetrics and Gynaecology, Lund University Hospital, Lund, Sweden b Centrum ambulantni gynekologie a porodnictvi, Brno, Czech Republic Division of Gynecology and Obstetrics ‘P Fioretti’, S.Chiara Hospital, University of Pisa, Pisa, Italy d Praxis f¨ ur Frauenheilkunde und Geburtshilfe, Wollankstrasse 11, Berlin, Germany e Osteoporoosiklinikka, Oulu, Finland f University Women’s Hospital, Tuebingen, Germany g Instytut Polozniczo Ginekologiczny Akademia Medyczna w lodzi, Lodz, Poland h Novartis Pharma AG, Basel, Switzerland Received 3 July 2006; received in revised form 19 December 2006; accepted 2 January 2007

Abstract Objective: To evaluate the safety and endometrial protection of low-dose transdermal estradiol (E2)/norethisterone acetate (NETA) patches (Estalis 25/125) in terms of post-treatment incidence of endometrial hyperplasia/cancer after 1 year of treatment in postmenopausal women with intact uteri. Methods: Patients were randomized to receive either transdermal E2/NETA (delivering daily doses of E2 25 ␮g and NETA 125 ␮g; applied every 3–4 days) or oral E2/NETA (E2 1 mg and NETA 0.5 mg; given daily) in this open-label study. The primary variable was the incidence of endometrial hyperplasia/cancer based on endometrial biopsies; secondary variables included vaginal bleeding/spotting patterns, patch adhesion, safety and tolerability. Results: Six hundred and seventy-seven patients were randomized (507 in the transdermal group and 169 in the oral group; one did not receive study drug) and >80% completed the study. There were no cases of endometrial hyperplasia or cancer in either group and the upper limit of the one-sided 95% confidence interval in the transdermal group was 0.85%. Over time, both treatments were associated with a decreasing frequency of spotting/bleeding days. The overall incidence of adverse events (AEs) was comparable in both groups, and the majority was mild-to-moderate in intensity. Breast tenderness was the most frequently reported AE (transdermal 19.9% versus oral 28.4%). AEs related to the gastrointestinal system were more frequent with oral E2/NETA, and episodes of spotting and bleeding were more frequent with transdermal E2/NETA. Local skin tolerability of the transdermal matrix system was good. ∗

Corresponding author at: Kvinnokliniken, Universitetssjukhuset, Lund SWE-221 85, Sweden. Tel.: +46 4617 1000; fax: +46 4615 7868. E-mail address: [email protected] (G. Samsioe).

0378-5122/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2007.01.001

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Conclusions: Transdermal E2/NETA (25 and 125 ␮g) provided adequate endometrial protection in postmenopausal women when evaluated according to CPMP/CHMP criteria, achieved a high rate of amenorrhea, and was well tolerated. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Endometrial safety; Estradiol; Norethisterone; Transdermal patch

1. Introduction The number of women who will live half their adult lives after the menopause increases every year [1]. Hormone replacement therapy (HRT) with estrogen is an effective treatment for the rapid relief of climacteric symptoms including those associated with vasomotor instability during the peri- and postmenopausal period [2,3]. However, treatment of menopausal symptoms with unopposed estrogen in women with an intact uterus can cause excessive stimulation of the endometrium, with a possible increased risk of endometrial hyperplasia [4] and/or endometrial cancer [5,6]. Progestogens – given as sequential or continuous combined therapy with estrogens – can help to prevent these adverse endometrial effects [7,8], and may also protect against the development of endometrial cancer [9,10]. As regular bleeding lowers compliance, the use of continuous combined estrogen/progestogen treatment has become popular as this approach results in amenorrhea [11]. In addition, the use of low-dose regimens has allowed treatment to be adapted to the individual needs of the patient [12]. HRT regimens are available in a range of dosage forms including oral tablets, topical creams, pessaries and transdermal patches. However, transdermal delivery of estrogen has a number of advantages over oral administration. Transdermal delivery provides a sustained release of estrogen with predictable absorption characteristics which provide a more physiological estrogen plasma profile, avoiding the peaks and troughs of oral therapy [13]. The transdermal route also avoids local gastrointestinal irritation, circumvents first-pass metabolism, and does not affect the biliary cholesterol saturation index [13–17]. However, problems of adhesion and skin tolerability with conventional transdermal patches can lead to poor compliance [18]. Transdermal matrix systems have been found to provide improved adhesion, tolerability and comfort [18,19]. The present study assessed the endometrial safety of treatment with a low-dose transdermal patch delivering

daily doses of estradiol (E2) 25 ␮g and norethisterone acetate (NETA) 125 ␮g (transdermal E2/NETA) for 1 year in postmenopausal women. Once-daily oral therapy with Activelle® (E2 1 mg plus NETA 0.5 mg (oral E2/NETA); Novo Nordisk, Denmark) was used as a comparator, as it is a low-dose formulation which contains the same active ingredients as transdermal E2/NETA.

2. Methods 2.1. Study design The primary objective of this open-label, multicenter study was to evaluate the safety and endometrial protection of low-dose transdermal E2/NETA 25/125 in terms of post-treatment incidence of endometrial hyperplasia/cancer after 1 year of treatment. An openlabel design was selected to improve compliance, which can be adversely affected in a double-blind, double-dummy design where placebo patches or tablets must be added to the active oral or transdermal treatments. Patients were recruited from 62 centers in 10 European countries (Austria (n = 5), Finland (n = 2), Germany (n = 19), Ireland (n = 2), Italy (n = 10), Czech Republic (n = 4), Poland (n = 2), Spain (n = 6), Sweden (n = 6), and Switzerland (n = 6)). The study comprised a 14-day screening period during which baseline endometrial thickness was assessed. In postmenopausal women with an endometrial thickness ≥5 mm as assessed by transvaginal sonography at screening, a progestogen test was performed followed by 7–10 days without any treatment in order to decrease endometrial thickness. The screening period was followed by 13 cycles (52 weeks) of treatment. Patients were randomized 3:1 to receive either the continuous combined transdermal matrix patch delivering lowdose E2/NETA (Estalis 25/125) applied every 3–4 days (i.e. twice weekly), or oral HRT (E2 1 mg and NETA 0.5 mg) given daily.

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2.2. Study population The study included healthy postmenopausal women (45–70 years) with an intact uterus, no natural menses for >1 year, and no previous treatment with HRT. Other inclusion criteria needed for randomization into the study included: follicle-stimulating hormone (FSH) ≥40 mIU/mL; uterus within normal limits for postmenopausal and endocrine status; clinically acceptable pelvic examination and cervical smear; baseline endometrial thickness <5 mm by vaginal ultrasound, or thickness <5 mm, 1 week after progestogen test; and sufficient endometrial tissue at biopsy for histopathological endometrial classification. Reasons for exclusion from the study included: undiagnosed vaginal bleeding, endometrial hyperplasia/cancer or endometrial polyps; a mammogram in the previous 12 months suggestive of malignancy and not excluded by histology; cardiovascular disease including uncontrolled hypertension, a history of myocardial infarction within the previous 12 months, uncontrolled/unstable angina pectoris or history of cerebrovascular infarction/stroke and confirmed/suspected active deep vein thrombosis or thrombophilic disorders and obesity (body mass index >30 kg/m2 ). The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice requirements, and was approved by the ethics committees at each center. All patients provided written informed consent before any study procedures were performed. 2.3. Assessments Pre-study assessments were made during the screening period. Baseline measurements were obtained at week 0 and follow-up assessments at weeks 4, 12, 24 and 52. 2.4. Primary variable The primary variable of the study was the incidence of post-treatment endometrial hyperplasia/cancer at 1 year based on the assessment of pre- and posttreatment endometrial biopsies. Biopsies were sent to a central laboratory and assessed by two different independent pathologists who were blinded to the treatment

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received. In case of disagreement between the pathologists, a third pathologist (also blinded) was called upon to make the final decision. Pathological evaluations were performed using the WHO classification system [20,21] for adequacy of material, functional status of endometrium, and hyperplasia, polyps and malignancies. 2.5. Secondary variables Bleeding patterns and patch adhesion were defined as secondary efficacy variables. Patients kept a diary to record bleeding (heavy/normal), spotting, or spotting and bleeding during the treatment phase, days when the patches were applied, and the number of patches falling off prematurely during the treatment cycle. The investigator also provided an assessment of patch adhesion. 2.6. Safety and tolerability All treatment-emergent adverse events (AEs) – serious and non-serious – together with their severity and presumed relationship to study drug were recorded. The occurrence of breast tenderness was recorded as an AE and assessed independently by the investigator. Skin tolerability at the application site was evaluated by the investigator using predefined rating scales. Hematology, blood chemistry and lipid profile analyses were performed at a central laboratory. The potential effects of low-dose oral versus transdermal HRT on coagulation factors associated with cardiovascular disease and venous thromboembolism were investigated in a subgroup of patients using blood samples drawn at baseline and at weeks 12 and 52. Transvaginal sonography, gynecological (pelvic) examination (including cervical smear), breast examination, mammography, electrocardiograms and measurements of vital signs were performed at regular intervals. Cervical smears were evaluated using the Bethesda System Classification. 2.7. Statistical analysis 2.7.1. Sample size At least 300 patients with pre- and post-treatment biopsies, treated for 1 year, were needed to evaluate the transdermal patch in terms of the endometrial safety

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requirements defined in the former and new European regulatory guidelines [22,23]. As it was not necessary to compare the incidence of hyperplasia between the treatment groups, a randomization ratio of 3:1 between transdermal E2/NETA 25/125 and Activelle® , respectively, was chosen. Based on a predicted drop-out rate of 35%, it was planned to include a total of 616 patients in the study. 2.7.2. Statistical methodology The incidence of endometrial hyperplasia/endometrial cancer was summarized using descriptive statistics and inference was based on the upper limit of a one-sided 95% confidence interval (CI), as defined in the former and new European regulatory guidelines [22,23]. These guidelines state that the incidence rate of endometrial hyperplasia/endometrial cancer should be <2% and that the upper limit of a onesided 95% CI should not exceed the point estimate by >2% in patients treated for 1 year. Exact CIs were calculated using the binomial distribution. Breast tenderness was analyzed using Fisher’s exact test, and the Kaplan–Meier method was used to obtain estimates of the time to first occurrence. Analysis of covariance (ANCOVA) for treatment effects was performed on changes in lipid values. Results were considered statistically significant if the P-value was found to be <0.05, although no adjustments for multiple comparisons (for the secondary variables) were performed. The non-parametric Wilcoxon rank sum test was applied to coagulation factors and lipid analysis markers. Other variables were summarized descriptively. The primary analysis was evaluated on a modified intent-to-treat (ITT) population, defined as all patients randomized who took treatment and had evaluable biopsies at baseline and at end of treatment (at least 11 cycles). Safety parameters were evaluated on all patients treated.

3. Results 3.1. Study population Overall, 677 patients were randomized into the study. A summary of patient flow is provided in Fig. 1.

Table 1 Demographic and background characteristics, all patients treated Variable (units)

Transdermal E2/NETA (n = 507)

Oral E2/NETA (n = 169)

Age (years) Mean (S.D.) Range <50 years, n (%) 50–65 years, n (%) >65 years, n (%)

56.1 (5.1) 45–70 39 (7.7) 447 (88.2) 21 (4.1)

56.1 (5.5) 45–69 16 (9.5) 144 (85.2) 9 (5.3)

Race, n (%) Caucasian Other

506 (99.8) 1 (0.2)

168 (99.4) 1 (0.6)

Body mass index (kg/m2 ) Mean (S.D.) 25.1 (2.9) Range 16.9–31.6

25.1 (3.0) 18.7–29.9

Weight (kg) Mean (S.D.) Range

66.6 (8.9) 42.0–99.0

66.8 (9.8) 44.5–93.0

FSH (mIU/mL) Mean (S.D.) Range

83.6 (28.9) 11–199

86.0 (32.6) 15–>200

Endometrial thickness (mm) Mean (S.D.) 2.7 (1.0) Range 0.3–4.9 Time from menopause (months) Mean (S.D.) 79.6 (58.5)a Range 12–341a a b

2.7 (1.0) 0.8–4.9 83.1 (60)b 12–240b

n = 502. n = 167.

The transdermal E2/NETA group included 507 patients and the oral E2/NETA group included 169 patients. One woman, randomized to the oral E2/NETA group, did not receive study drug and was therefore excluded from the analyses. More than 80% of patients completed the study: 81% (412/507) of those receiving transdermal E2/NETA and 82% (139/169) of those receiving oral E2/NETA. The key demographic and background characteristics of the two treatment groups were comparable (Table 1). The mean duration of treatment was 325.3 days (standard deviation, [S.D.]: 96.2 days) with transdermal E2/NETA, and 320.7 days (S.D.: 99.6 days) with oral treatment. Treatment compliance was 99.3% and 98.8%, respectively. The majority of patients (86.0% transdermal and 84.0% oral) had a physiological or medication-induced atrophic endometrium at baseline. A marginally or weakly proliferative

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Fig. 1. Summary of patient flow.

endometrium at baseline was reported for 10.1% and 13.6% of patients in the transdermal and oral groups, respectively. The majority of patients also had a normal cervical smear at baseline. Clinically insignificant abnormalities were present in 6.3% and 7.7% of

patients in the two groups, respectively. Mammography at screening revealed normal results in 84% of patients receiving transdermal E2/NETA and in 86% of patients receiving oral treatment; none of the abnormalities were clinically significant.

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3.2. Endometrial safety

were the only exceptional clinical findings identified in the post-baseline biopsy.

After 1 year of treatment, there were no cases of endometrial hyperplasia or cancer in either treatment group (point estimate for the incidence rate of endometrial hyperplasia or cancer in the trandermal group: 0.00%; upper 95% CI: 0.85%). This satisfies the CPMP and CHMP requirements for endometrial safety [22,23]. Mean endometrial thickness at baseline was comparable in the two treatment groups (Table 1). Small and comparable increases in endometrial thickness were seen with both formulations: mean values at end of treatment were 3.1 mm (S.D. = 2.1) and 3.2 mm (S.D. = 1.5) with transdermal and oral therapy, respectively. An endometrial thickness ≥5 mm at end of treatment was noted in 10.5% of women receiving transdermal therapy and 11.5% of women receiving oral E2/NETA. Results for the last post-baseline biopsy in patients in the ITT population are shown in Table 2. Most patients in both groups showed an atrophic endometrium at the end of the study. The proportion of patients categorised as having a marginally/weakly proliferative endometrium at the end of the study was higher with transdermal (13.9%, 49 patients) than with oral (3.3%, four patients) estradiol-NETA, although this result was not found to be statistically significant. The occurrence of a marginally/weakly proliferative endometrium at baseline was similar in the two groups. Amongst all patients treated, six cases of endometrial polyps (four (1.0%) with transdermal and two (1.5%) with oral estradiol-NETA; safety population) Table 2 Functional status of the endometrium at study endpoint, ITT population Endometrial status, n (%)

Transdermal E2/NETA (n = 352)

Oral E2/NETA (n = 122)

Physiological or medication-induced atrophy Marginal/weakly proliferative Regular proliferative Irregular disordered proliferative Secretory Missing assessment

291 (82.7)

116 (95.1)

49 (13.9) 1 (0.3) 2 (0.6)

4 (3.3) 0 (0.0) 0 (0.0)

7 (2.0) 2 (0.6)

1 (0.8) 1 (0.8)

3.3. Bleeding pattern Both treatments resulted in a decreased frequency of spotting and bleeding days: a reduction from a mean number of 5.8 days (cycles 1–3) to 2.4 days (cycles 10–12) for the transdermal group, and 4.9–1.8 days, respectively, for the oral group. Accordingly, the percentage of amenorrheic patients in the transdermal group increased from 59% in cycles 1–3 to 80% in cycles 10–12, and 86% of patients were amenorrheic by cycle 13. This compared with 68%, 88% and 97%, respectively, for the oral group. The proportion of bleed-free patients (i.e. patients without inter-menstrual bleeding) with the transdermal system increased from 81% in cycles 1–3 to 94% in cycles 10–12 (Table 3), and 98% were bleed-free by cycle 13. This compared with 85%, 95% and 99%, respectively, for the oral group. 3.4. Adverse events The overall incidence of AEs was comparable in both groups (64.9% and 66.3% for transdermal and oral estradiol-NETA, respectively); AEs with an incidence ≥2% in any group are summarized in Table 4. The majority of AEs in both groups were of mild-tomoderate intensity. The incidence of severe AEs was low in both groups (5.1% and 3.6% for transdermal and oral estradiol-NETA, respectively). The most frequently reported AE was breast tenderness, which occurred with a lower incidence with transdermal (19.9%) than with oral (28.4%) E2/NETA. A separate evaluation derived from the investigator’s overall interpretation also showed that breast tenderness was lower with transdermal E2/NETA compared with oral E2/NETA (20.3% versus 28.7%; P = 0.0249). Table 3 Number of bleed-free patients by quarter, all patients treated Period

Transdermal E2/NETA, n (%)

Oral E2/NETA, n (%)

Cycles 1–3 Cycles 4–6 Cycles 7–9 Cycles 10–12

411/505 (81.4) 396/462 (85.7) 389/433 (89.8) 389/414 (94)

142/167 (85) 139/153 (91.4) 139/146 (95.2) 135/142 (95.1)

G. Samsioe et al. / Maturitas 57 (2007) 171–181 Table 4 Summary of AEs occurring in at least 2% of patients in one of the treatment groups AEa summary

Transdermal E2/NETA (n = 507)

Oral E2/NETA (n = 169)

Patients with AEs, n (%) 329 (64.9)

112 (66.3)

AE (MedDRA preferred term), n (%) Breast tenderness 101 (19.9) Headache 34 (6.7) Nasopharyngitis 26 (5.1) Vaginal hemorrhage 23 (4.5) Uterine hemorrhage 18 (3.6) Influenza 14 (2.8) Back pain 13 (2.6) Cystitis 12 (2.4) Weight increased 12 (2.4) Dysmenorrhea 10 (2.0) Abdominal pain 9 (1.8)

48 (28.4) 10 (5.9) 12 (7.1) 3 (1.8) 2 (1.2) 10 (5.9) 5 (3.0) 1 (0.6) 4 (2.4) 0 6 (3.6)

a Irrespective of any suspected relationship to study drug medication.

In addition, in this evaluation, the onset of breast tenderness was later with transdermal E2/NETA (299 days versus 257 days; P = 0.0209, Fig. 2). Hemorrhagic AEs related to the reproductive tract included mainly vaginal hemorrhage – 4.5% transdermal and 1.8% oral; uterine hemorrhage – 3.6% transdermal and 1.2% oral; metrorrhagia – 1.8% transdermal and 0% oral; postmenopausal hemorrhage – 0.6% transdermal and 0.6% oral. The majority of these AEs was mild-to-moderate in nature and resulted in 3.6% and 1.8% of patients discontinuing in the transdermal and oral groups, respectively. AEs related to the gastrointestinal system were more frequent with oral estradiol-NETA: abdominal pain –

Fig. 2. Time to first occurrence of breast tenderness (Kaplan–Meier estimates).

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1.8% transdermal and 3.6% oral; upper abdominal pain – 1.0% transdermal and 1.8% oral; constipation – 0.2% transdermal and 1.2% oral; and dyspepsia – 0.2% transdermal and 1.2% oral. There were no deaths during the study. The incidence of serious AEs was comparable between the two groups (transdermal E2/NETA, 3.7%; oral E2/NETA, 2.4%). Mammography revealed one case of breast cancer for the oral E2/NETA group, 4 weeks after the patient discontinued treatment. None were reported for the transdermal group. Five additional patients had significantly abnormal mammography findings (assessed at end point or up to 30 days’ post-treatment discontinuation); two patients receiving transdermal E2/NETA (microcalcification and cysts) and three in the oral E2/NETA group (fibroadenoma, fibrocystic mastoiditis, and proliferation of gland tissue). AEs that resulted in discontinuation of study medication occurred in 14.6% of patients receiving transdermal and 12.4% of patients receiving oral estradiol-NETA. Local skin tolerability of the transdermal matrix system was good. The majority of patients treated with transdermal E2/NETA reported no local skin irritation, and 83% of women had no erythema by week 52 (although there was considerable variability by study site). Only 5.9% of patients discontinued treatment due to skin irritation. Additionally, 92% of patches remained completely adhered to the skin at the end of the study (investigator’s assessment). 3.5. Hematology and clinical biochemistry Hematological parameters were comparable at baseline, and there were no clinically meaningful differences between treatment groups at the end of treatment for any of the parameters. In addition, there were no clinically meaningful trends or differences between the treatment groups for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, lactate dehydrogenase, creatinine, urea, uric acid, glucose and insulin. Baseline values were comparable for all lipid parameters investigated (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, apolipoprotein A1 and B, triglycerides and lipoprotein (a)) (Table 5). A slight decrease in mean total cholesterol was observed

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Table 5 Summary of the lipid analysis Parameter

E2/NETA group Transdermal

Total cholesterol (g/L) HDL cholesterol (g/L) LDL cholesterol (g/L) Apolipoprotein A1 (g/L) Apolipoprotein B (g/L) Triglycerides (g/L) Lipoprotein (a) (g/L)

Oral

Baseline

Endpoint

Baseline

Endpoint

2.26 0.68 1.35 1.72 1.04 1.15 0.25

2.15 0.67 1.27 1.58 0.94 1.03 0.22

2.26 0.68 1.35 1.74 1.06 1.16 0.27

2.07 0.63 1.21 1.57 0.93 1.09 0.21

Mean (LS) difference (transdermal–oral) in change from baseline (95% CI)

P value

0.089(0.044,0.133) 0.036(0.018,0.053) 0.07(0.031,0.109) 0.02(–0.02,0.06) 0.02(–0.01,0.05) –0.05a (–0.11,0.0) 0.02(0.01,0.04)

<0.0001 <0.0001 0.0005 0.2855 0.1408 0.0665 0.0047

LS: least squares. a Median value.

in both treatment groups at the end of treatment (−0.11 g/L transdermal and −0.2 g/L oral estradiolNETA). Similarly, mean triglycerides decreased by −0.12 and −0.07 g/L in the two groups, respectively. Mean HDL cholesterol remained almost unchanged (−0.01 and −0.04 g/L, respectively), but there was a slight decrease in mean LDL cholesterol (−0.07 and −0.14 g/L, respectively). Small mean decreases were also seen for apolipoprotein A1 and B and for lipoprotein (a). The magnitude of these changes was similar in both groups. The incidence of abnormal lipid values of note was comparable between treatment groups for all lipid parameters except LDL cholesterol where values >1.60 g/L were seen in 19.2% of patients receiving transdermal E2/NETA group and in 12.2% of patients receiving oral therapy.

Oral and transdermal estradiol-NETA generally had similar effects on coagulation (Table 6) with both being associated with decreased factor VII and antithrombin III. Fibrinogen only decreased with the oral preparation but, as indicated by prothrombin fragment measurement, there were no significant changes in overall coagulation activation in either group. Reduced plasmin–antiplasmin complex with transdermal estradiol-NETA indicated that the overall level of in vivo fibrinolytic activation may have been reduced in this group. In contrast, this coagulation parameter remained unchanged in the oral estradiolNETA group but plasminogen activator inhibitor type 1 decreased, resulting in a statistically significant difference between the groups. The clinical significance of these findings is unknown.

Table 6 Summary of the coagulation factor analysis Parameter

E2/NETA group Transdermal

Fibrinogen (g/L) Factor VII (%) Antithrombin III (%) APC resistance Prothrombin fragment F1.2 (nmol/L) Plasmin-antiplasmin complex (␮g/L) PAI-1 antigen (ng/mL) tPA antigen (ng/mL)

Oral

Baseline

Endpointa

Baseline

Endpointa

2.80 109 108 2.80 0.97 402 20.81 9.17

2.81 103 103 2.85 1.07 378 20.67 8.41

2.82 110 107 2.80 1.00 383 20.78 8.57

2.76 100 102 2.84 1.13 397 17.03 8.57

Median difference (transdermal–oral) in change from baseline (95% CI)

P value

0.054 (−0.002,0.115) 3.6 (1.2, 6.3) 1.5 (−0.9, 3.9) 0.05 (−0.08, 0.18) −0.01 (−0.11, 0.09) −43.8 (−73.1, −11.6) 3.9 (0.40, 7.22) −0.01 (−0.80, 0.81)

0.060 0.006 0.214 0.401 0.895 0.008 0.029 0.991

APC = activated protein C; PAI-1: plasminogen activator inhibitor type 1; tPA: tissue plasminogen activator. a Week 24.

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3.6. Other physical findings No statistically significant or clinically meaningful difference was found between the two groups with respect to changes in vital signs during the 1 year study. The results of the pelvic examination (external genitalia, vagina, cervix, uterus, ovaries and abdominal examination) and breast examination did not reveal any differences of note between treatment groups. Significant clinical abnormalities as assessed by the investigator occurred in very few patients in either treatment group; six cases in the transdermal E2/NETA group (external genitalia (n = 2), vagina (n = 1), cervix (n = 1), uterus (n = 1), ovaries (n = 1)) and three cases in the oral E2/NETA group (vagina (n = 1), uterus (n = 1), and breast (n = 1)). Significantly abnormal cervical smear findings occurred in three patients receiving transdermal E2/NETA and in one patient receiving oral estradiolNETA. In all four cases, these findings were attributed to benign cellular changes resulting from infection.

4. Discussion The present study indicates that a low-dose continuous combined transdermal matrix patch system delivering E2/NETA provides adequate long-term endometrial protection when evaluated according to CPMP and CHMP criteria [22,23]. No cases of endometrial hyperplasia were observed in the 507 subjects with evaluable biopsies after a minimum of 12 treatment cycles. These results are in line with those of a long-term study using the low-dose transdermal E2/NETA reservoir patch system [24]. Amenorrhea commonly occurs with long-term administration of a continuous combined HRT regimen, and any bleeding or spotting is considered irregular. The bleeding data from this study confirm this expectation. The study results also confirm that a continuous combined transdermal matrix patch system delivering low-dose E2/NETA can result in amenorrhea in a significant proportion of patients. Over 80% of women reported no bleeding during the first 3 months of treatment, and over time, treatment was associated with a further decrease in frequency of bleeding days. The control of bleeding seen with the low-dose trans-

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dermal patch compares favorably with the use of a continuous low-dose transdermal reservoir system [24] and the best reported continuous combined regimens [25,26]. The high rate of amenorrhea together with improved adhesion and better skin tolerability seen with this transdermal HRT system may further improve patient compliance. AEs reported for the low-dose transdermal E2/NETA were of mild-to-moderate intensity. Breast tenderness occurred less frequently with transdermal E2/NETA than with oral estradiol-NETA, both when assessed as an AE and when evaluated independently by the investigator. Also, the onset of breast tenderness was later with transdermal treatment. This observation may reflect differences in systemic availability between the two routes of administration. In addition, gastrointestinal disorders were somewhat more frequent in the oral E2/NETA group. Although hemorrhagic AEs related to the reproductive tract appeared to have a slightly higher incidence among patients receiving transdermal estradiol-NETA, it should be noted that a 3:1 randomization in favor of this group was employed which could bias findings. More patients receiving transdermal treatment also showed a marginal or weakly proliferative endometrium at end of treatment, although this difference was not significant. Of note, no increase in the risk of developing hyperplasia has been reported for such patients with this endometrial status [8,27]. A diagnosis of breast cancer was made approximately 4 weeks after discontinuation of study medication in a patient aged 55 years previously included in the oral E2/NETA group. In addition to the 3:1 randomization schedule used in the study, this incidence falls in line with that expected, given the age of the patient and the expected background rates for this age group [28]. The results also confirm the beneficial effects of HRT on total cholesterol, HDL cholesterol, LDL cholesterol, apolipoprotein A1 and B, triglycerides and lipoprotein (a). The observed decreases were generally comparable between treatment groups, except for the decreases in total cholesterol values, which were more marked with oral estradiolNETA. In summary, these findings suggest that a continuous combined transdermal matrix patch delivering low-dose E2/NETA can be safely used as HRT in post-

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menopausal women and is well tolerated. This low dose maintained a consistently high rate of amenorrhea in postmenopausal women.

Acknowledgements Editorial and project management services were provided by ACUMED® . The authors are grateful for the support of the following investigators/coinvestigators in this study: Sepp Leodolter, Paul Riss, Hans Concin, Wolfgang Urdl, Nora Donatova, Ivo Blstak, Vladislav Klimes, Boguslaw Lemieszczuk, Erkki Hirvonen, Hartmut Hommel, Holger Thelen, Jan Bakowski, Hans-Peter Materna, Detlef Rautenberg, Kuno Wetzel, Klaus Doensch, Lutz Weihe, Wolfgang Klempp, Bjoern Kahoun, Robert Landthaler, Heinz Litschmann, Ulrich Schreiber, Peter Siegler, Gerhard Schmid, Edeltraud Weiss, Axel Gerick, Thomas Fuesslin, Brian Sheppard, Colm O’Herlihy, Francesco Saverio Pansini, Alberto Bacchi-Modena, Giambattista Massi, Michele Gangemi, Sergio Messini, Franco Polatti, Giovanni Salvatore Sciacchitano, Luigi Frigerio, Francesco Cancellieri, Amilcare Meneghel, Magdalena Duran, Antonio Cano Sanchez, Maria de la Misericorda Guinot Casull, Javier Ferrer Barriendos, Antonio de Castro Perez, Antonio Estevez Gonzalez, Eva Peter-Lingman, Tommy Sporrong, Arne Eliasson, Sverker Toernudd, Christian De Geyter, Michael Kurt Hohl, Hanspeter Vogt, Thierry Pache, David Stucki, Martin Hans Birkhauser. Source of funding: This study and publication was funded by Novartis Pharma AG.

References [1] World Health Organization. Research on the menopause in the 1990s. WHO Tech Rep Ser 1996; No. 866. [2] Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet 2002;360:1851–61. [3] Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol 2004;190:1141–67. [4] Lethaby A, Suckling J, Barlow D, Farquhar C, Jepson R, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev 2004;3. [5] Diamanti-Kandarakis E. Hormone replacement therapy and risk of malignancy. Curr Opin Obstet Gynecol 2004;16:73–8.

[6] Emons G, Huschmand-Nia A, Krauss T, Hinney B. Hormone replacement therapy and endometrial cancer. Onkologie 2004;27:207–10. [7] Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the women’s health initiative randomized trial. JAMA 2003;290:1739–48. [8] Wells M, Sturdee DW, Barlow DH, et al. Effect on endometrium of long-term treatment with continuous combined oestrogen–progestogen replacement therapy: follow up study. BMJ 2002;325:239–42. [9] Hill DA, Weiss NS, Beresford SA, et al. Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Obstet Gynecol 2000;183:1456–61. [10] Weiderpass E, Adami HO, Baron JA, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131–7. [11] Mattsson LA, Sporrong T. Low dose hormone replacement therapy: clinical efficacy. Minerva Ginecol 2003;55:201–7. [12] Shoupe D. HRT dosing regimens: continuous versus cyclic-pros and cons. Int J Fertil Womens Med 2001;46:7–15. [13] Crust M, Gangar K, Whitehead M. Administration of steroids by skin patches. Res Reprod 1989;21:1–2. [14] Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17␤-estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol 1985;152:1099–106. [15] Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol 1990;75:S9–14. [16] Cedars MI, Judd HL. Non-oral routes of estrogen administration (review). Obstet Gynecol Clin North Am 1987;14:269–98. [17] Van Erpecum KJ, Van Berge Henegouwen GP, Verschoor L. Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women (review). Gastroenterology 1991;100:482–8. [18] Stevenson JC. Optimising delivery systems for HRT. Maturitas 1999;33(Suppl. 1):S31–8. [19] Rozenbaum H, Birkhauser M, De Nooyer C, et al. Comparison of two estradiol transdermal systems (Oesclim 50 and Estraderm TTS 50). Tolerability, adhesion and efficacy. Maturitas 1996;25:161–73. [20] Dallenbach-Hellweg G, Poulsen H. Atlas of endometrial histopathology. 2nd ed. Berlin: Springer; 1996. [21] Kurmann RJ, editor. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer Verlag; 1994. [22] Committee for Proprietary Medicinal Products (CPMP) Guideline. Points to consider on hormone replacement therapy (CPMP/EWP/021), London, UK. November 19, 1997. [23] Committee for Medicinal Products for Human Use (CHMP) Guideline. Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. May 1, 2006. http://tga.health.gov.au/docs/pdf/euguide/emea/002197enrev1. pdf. [24] Brynhildsen J, Hammar M. Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not

G. Samsioe et al. / Maturitas 57 (2007) 171–181 cause endometrial proliferation in postmenopausal women. Menopause 2002;9:137–44. [25] Sporrong T, Hellgren M, Samsioe G, Mattsson LA. Comparison of four continuously administered progestogen plus oestradiol combinations for climacteric complaints. Br J Obstet Gynaecol 1988;95:1042–8. [26] Von Holst T, Rakov V, Kretschmar S. Amenorrhea rate after switch from sequential hormone replacement therapy

181

to continuous combined administration of low dose estradiol and norethisterone acetate. Zentralbl Gynakol 2002;124: 368–73. [27] Feeley KM, Wells M. Hormone replacement therapy and the endometrium. J Clin Pathol 2001;54:435–40. [28] American Cancer Society. Cancer facts and Figures 2004. Atlanta, GA, USA: American Cancer Society Inc., 2004:14 (www.cancer.org/downloads/STT/CAFF finalPWSecured.pdf).