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levonorgestrel patch in women
Maturitas 41 (2002) 231– 242 www.elsevier.com/locate/maturitas
Efficacy of a new 7-day transdermal sequential estradiol/levonorgestrel patch in women Thomas von Holst *, Birgitt Salbach Uni6ersity Gynecological Clinic, Ruprecht-Karl Uni6ersity, Voßstrasse 9, D-69115 Heidelberg, Germany Received 15 May 2001; received in revised form 24 October 2001; accepted 6 November 2001
Abstract Objecti6e: To investigate the efficacy and tolerability of a new 7-day transdermal sequential estradiol/levonorgestrel patch (Fem7® Combi; Merck KGaA; Germany), versus placebo, as hormone replacement therapy in menopausal women. Methods: A multicentre, randomized, clinical study consisting of a 3-week screening phase, a 12-week double-blind, placebo-controlled treatment phase, and a 12-week open, follow-up phase. Women aged 40 – 65 years with an intact uterus and menopausal complaints were randomized to either 2 weeks of an estradiol mono patch (50 mg per 24 h) followed by 2 weeks of an estradiol/levonorgestrel combination patch (50 mg/10 mg per 24 h), or a placebo patch, for three 28-day cycles. Changes in the Kupperman Index and the frequency of hot flushes were assessed. Results: The sequential use of a 7-day estradiol patch and a 7-day estradiol/levonorgestrel patch was superior to placebo in reducing menopausal symptoms, and was well tolerated. At the end of the treatment phase, there was a statistically significant reduction in the Kupperman Index score versus placebo (P B 0.0001), and a statistically significant difference between groups in the proportion of patients with a reduction in the number of hot flushes (at least 50% versus baseline). During the open follow-up phase, there was a marked reduction in the Kupperman Index score and the number of hot flushes for patients switched from placebo to active study medication. The active medication was effective throughout the 1-week application period. Conclusions: The new 7-day transdermal sequential estradiol/levonorgestrel patch was well tolerated, providing rapid and effective relief of menopausal symptoms. The addition of low-dose levonorgestrel did not influence the beneficial effects of estradiol. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 7-Day-estradiol patch; 7-Day-estradiol/levonorgestrel patch; Transdermal sequential regimen; Estradiol; Levonorgestrel; Kupperman index; Hormone replacement therapy
1. Introduction Estrogen is an effective treatment for the climacteric symptoms and complaints associated * Corresponding author. Tel.: + 49-6221-567-856; fax: + 49-6221-565-713.
with menopause [1], of which vasomotor disorders (hot flushes) are the most frequent and particularly distressing. In recent years it has also become clear that estrogen can provide important additional health benefits by reducing cardiovascular morbidity and mortality [2,3] and preventing osteoporosis [4–10] in postmenopausal women.
0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 1 ) 0 0 2 9 7 - 3
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The transdermal administration of hormone replacement therapy has several advantages over oral administration. Oral estrogen undergoes substantial conversion to inactive metabolites in the gastrointestinal tract and substantial first-pass hepatic metabolism. Much lower doses of medication are effective with transdermal delivery because this inactivation and metabolism are avoided [11]. Patients receiving transdermal estrogen replacement therapy report fewer gastrointestinal adverse events (e.g. nausea, vomiting, abdominal pain), which may be directly related to the oral route [12] and also have a reduced risk of increased smooth muscle tone, gall bladder disease and venous thrombosis [13]. However, skin reactions (e.g. erythema and pruritus at the application site) might occur with transdermal delivery systems [14]. With the patch delivery, the risk of cardiovascular disease associated with insulin resistance is reduced compared with oral administration, as glucose metabolism is improved [15,16]. Transdermal delivery does not affect serum triglyceride levels, which are considered an independent risk factor for cardiovascular disease which may increase with oral estrogen therapy [17– 19]. Unopposed estrogen therapy is only used to treat women who have undergone a hysterectomy, because although estrogen minimizes the effects of menopausal symptoms, it stimulates the growth of endometrial tissue in the uterus and prolonged treatment is known to induce endometrial hyperplasia [20–22]. The addition of progestogen protects the endometrium from hyperplasia, effectively preventing endometrial cancer [23– 25]. Bleeding can be a reason for discontinuing hormone replacement therapy (HRT), especially since the bleeding can be unpredictable. The use of progestogen and estrogen together in a sequential treatment regimen should result in an acceptable bleeding pattern, which is an important consideration for continuation of therapy [11]. Combination therapy with estrogen and progestogen is, therefore, the most widely prescribed therapy for women who still have an intact uterus. There are, however, some concerns that the addition of progestogen may counteract the beneficial effects of estrogen on lipid
metabolism and in addition, cause premenstrual symptoms such as bloating, depression and headache [11], as well as other side effects. The objective of this clinical study was to investigate the efficacy and tolerability of the sequential use of two transdermal systems, a 7-day-estradiol patch and a 7-day-estradiol/ levonorgestrel patch (Fem7® Combi; Merck KGaA; Germany), compared with placebo, as cyclic hormonal replacement therapy in women with menopausal complaints. These patches only have to be changed every 7 days as opposed to every 3–4 days for other currently available patches. The unique patented matrix technology of the patches used in this study, which is based on styrene–isoprene–styrene (SIS) block copolymers, enables hormones to penetrate the skin without the need for permeation enhancers and thus reduces the likelihood of skin reactions, allowing the use of the lowest estradiol loading charge. This, combined with the 7-day application period, may offer the possibility of improved patient compliance compared with currently available sequential regimens.
2. Patients and methods
2.1. Study design This was a multicentre, randomized, clinical study consisting of an initial 3-week screening phase without study medication, followed by a 12-week double-blind, placebo-controlled phase, and a 12-week open follow-up phase during which all patients were treated with active medication. The placebo-controlled and follow-up phases were each divided into three 28-day (4-week) cycles. Patients were assessed prior to randomization, at entry into the study at 4, 12, 16, and 24 weeks, and at the end of the study.
2.2. Patients Women aged 40–65 years with an intact uterus and menopausal complaints were included in the study. Patients were in either a physiological postmenopausal state (last regular menstruation more
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than 12 months prior to inclusion in the study) or a surgical postmenopausal state (bilateral oophorectomy more than 3 months prior to inclusion in the study). Patients were required to have a normal gynaecological history and examination, serum estradiol (E2) levels less than 30 pg/ml, and follicle stimulating hormone (FSH) levels greater than 30 IU/l. Women who were randomized had experienced at least 15– 20 hot flushes per week within the month prior to screening and had an overall Kupperman Index score of \20 (the maximum possible Kupperman Index score is 51). Patients treated with oral sex hormones within the last 28 days, locally applied sex hormones within 21 days, or injectable sex hormones within 6 months prior to the start of the study were excluded from participating. The study was carried out in accordance with Good Clinical Practice and the Declaration of Helsinki as amended in Hong Kong (1989). All patients gave their written, informed consent to participate in the clinical study.
2.3. Medication Study medication consisted of the following: 7-day estradiol patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol per 24 h); 7-day estradiol/levonorgestrel patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol per 24 h; 1.5 mg levonorgestrel with a delivery rate of approximately, 10 mg levonorgestrel per 24 h); matching placebo monotherapy patch, or matching placebo combination therapy patch. No medication was administered during the initial screening phase, which was performed within the 3 weeks prior to randomization. During the double-blind, placebo-controlled phase, the following medication was administered during each of the three 28-day cycles: either the 7-day estradiol patch for 2 weeks followed by the 7-day estradiol/levonorgestrel patch for 2 weeks, or the placebo monotherapy patch for 2 weeks followed by the placebo combination therapy patch for 2 weeks. During the open follow-up phase, all patients received active drug therapy (the 7-day estradiol patch for 2 weeks followed by the 7-day
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estradiol/levonorgestrel patch for 2 weeks) for a further 12 weeks (three 28-day cycles). The patches used in this study comprised a thin, flexible, transparent film in an octagonal shape approximately 15 cm2 in size. The release liner comprised a thicker, less flexible transparent film, square in shape with a punched cut to assist removal. The unique patented matrix technology of these patches, which is based on SIS block copolymers, allows estradiol to penetrate the skin without the need for permeation enhancers.
2.4. Efficacy 6ariables Patients reported the presence and severity of menopausal symptoms for the interval between visits by means of the Kupperman Index [26]. Patients used diary cards to report the daily frequency of hot flushes. The primary efficacy variable in the present study was the change from baseline in the Kupperman Index score at the end of the placebo-controlled phase (following 12 weeks of treatment). Secondary efficacy variables included the change from baseline in the Kupperman Index score for cycles 1, 3, 4, and 6, and at study endpoint, the number of hot flushes per week (days 1–3 and days 4–7) compared with baseline values and the number of patients with a greater than 50% reduction in the number of hot flushes per week.
2.5. Safety assessments Skin tolerability was assessed by the investigator on the basis of two 5-point scales (one for erythema and one for oedema), using a modified assessment system [27]. The occurrence of skin reactions e.g. redness/swelling or itchiness at the site of patch application was also recorded by the patient at the end of each application period and the incidence of skin reactions was assessed against the number of patches applied. Patients underwent a gynaecological examination (vagina, mammae and cytological smear) at both the start of and end of the study. Endometrial height was sonographically determined at the beginning of the study, at the end of the treatment phase and at the end of the study.
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Haematology, biochemistry, and serum lipid profile samples were assessed in fasting condition before enrolment, and after 3 (lipid profile only) and 6 cycles of therapy. All adverse events were recorded whether reported by the patient or observed by the investigator, including haematology and serum biochemistry data, irrespective of any causal relationship with the study drugs.
2.6. Other assessments Patch adhesiveness was assessed by the investigator at weeks 4, 12, 16, and 24, and rated as clinically adequate (degree of detachment 5 40%) or clinically inadequate (degree of detachment \ 40%). The patient also assessed adhesiveness on a weekly basis at the end of each application period. Handling, appearance and convenience of the patch were rated by the patient as very good, good, moderate, or poor at the end of cycle 2 and at the end of the study. In addition, patients were requested to indicate whether they would continue using the patch after the study. Counting the unused medication returned by the patients assessed compliance with medication.
2.7. Statistical methods For continuous data, treatment groups were compared using the two-tailed Wilcoxon ranksum test. To allow for a meaningful clinical interpretation of results, differences between groups were based on a one-way analysis of variance. Response rates were analyzed by means of Fisher’s Exact test. All statistical tests were two-sided with a 5% significance level. The intention-to-treat (ITT) population was used to analyze efficacy data during the double blind, placebo-controlled phase of the study. Patients qualified for the ITT population if they had been treated with the study medication at least once and had provided any follow-up data for one or more target efficacy variables. In this context, missing values were replaced using LOCF (last observation carried forward) methodology.
3. Results
3.1. Subjects A total of 216 patients from 33 centers were enrolled. Thirty-seven patients withdrew prior to randomization— most did not meet the inclusion criteria (particularly with regard to baseline hormone concentrations). A total of 179 women (n = 87, active therapy; n= 92, placebo therapy) were then randomized to the double-blind treatment phase. Estradiol and follicle stimulating hormone levels during randomization were comparable between the treatment groups. Both groups were well matched in terms of demographic data and baseline values for the Kupperman Index and in terms of complaint scores regarding the urogenital system, whereas the weekly number of hot flushes was higher at baseline in the active medication group. Mean age was 53.5 and 53.1 years in the active medication and placebo groups, respectively. In total, 31 patients withdrew from the study during the placebo-controlled phase (15 in the active treatment group and 16 in the placebo group), eight of whom were withdrawn due to adverse events, which was the most frequent reason for patient withdrawal. A total of 149 patients, therefore, entered the open follow-up phase (72 patients who remained on active treatment and 76 patients who were switched from placebo to active medication).
3.2. Efficacy Mean baseline values for the Kupperman Index were similar in the two treatment groups (mean values were 26.3 in the active medication group and 27.1 in the placebo group) and indicated moderate-to-severe climacteric complaints; individual values were as high as 44 in the active medication group and 41 in the placebo group. In both groups, reductions in the Kupperman Index score versus baseline were observed throughout the placebo-controlled phase, although these reductions were the greatest in the group receiving active therapy (Fig. 1).
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Fig. 1. Mean values of Kupperman Index for the new 7-day transdermal sequential system: a 7-day-estradiol patch and a 7-day-estradiol/levonorgestrel patch, and placebo over three cycles (Phase II, placebo-controlled phase).
The difference between treatment groups for the primary efficacy variable (change in Kupperman Index score at the end of the placebo-controlled phase versus baseline) was statistically significant in favor of the active medication group (P= 0.0001), with the mean value of the Kupperman Index score declining from 26.3 to 9.5 in the active treatment group and from 27.1 to 15.9 in the placebo group. The mean difference between groups concerning changes in Kupperman Index score at the end of the placebo-controlled phase versus baseline was 5.6 (95% CI 3.08– 8.13). The open follow-up phase showed that early treatment effects were maintained with prolonged active therapy (Table 1). A marked reduction in the Kupperman Index score was observed when placebo patients were switched to active medication during the follow-up phase (Table 1). At the end of this phase, the Kupperman Index scores were significantly reduced (P B0.01), irrespective of whether patients received placebo or active medication during the placebo-controlled phase. Unlike the Kupperman Index scores, the mean weekly number of hot flushes at baseline was higher in the active medication group compared with the placebo group (49.4 vs. 40.0). However, a distinctive difference in the reduction of hot
flushes from baseline between the active medication and placebo recipients was noted from week 2 of treatment throughout the placebo-controlled phase, with differences being significant in favor of the active treatment at weeks 4, 8, and 12 (Fig. 2), confirming the rapid onset of action of Fem7® Combi. Table 1 Demographic data — ITT population Active (n =84) Age (mean 9 SD; years) Height (mean 9SD; cm) Weight (mean 9 SD; kg) Non-smokers (patients) Kuppermann index (mean 9SD) Urogenital system complaint score (mean 9SD) Weekly hot flushes (mean 9SD; patients)
Placebo (n = 88)
53.5 94.83
53.1 95.35*
164.2 95.70
163.3 9 6.20
66.18 98.740
66.81 9 9.737*
55 (65.5%)
60 (68.22%)*
26.3 95.21
27.1 95.10
2.4 91.84
2.6 91.99
49.4 945.14**
*P=NS; **n= 74; †n =78.
40.0 921.62†
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Fig. 2. Weekly frequency of hot flushes for the new 7-day transdermal sequential system, a 7-day-estradiol patch, and a 7-day-estradiol/levonorgestrel patch versus placebo over 12 weeks. Between-group comparisons: Pweek4 =0.0003; Pweek8 =0.0001; Pweek12 =0.0002 (Phase II, placebo-controlled phase).
The difference between the groups at the end of the placebo-controlled phase with regard to changes from baseline was estimated to be 21.47 hot flushes per week (95% CI 10.56– 32.38), again showing a significant difference between treatments in favor of the active medication group. At the end of the open follow-up phase, the mean number of hot flushes was shown to be further reduced to 5.1 per week in the group who received active medication throughout the study, and 5.5 per week in the group who switched from placebo to active therapy at the beginning of the follow-up phase. Considerably more patients on active medication compared with placebo experienced a clinically relevant and statistically significant reduction in the number of hot flushes by at least 50% compared with baseline in the placebo-controlled phase of the study (81.16% reduction versus 57.33%; P= 0.0023). By separating the results for days 1–3 (Fig. 3a) and 4– 7 (Fig. 3b) of treatment with active medication, it was further shown that efficacy, in terms of the frequency of hot flushes, could be maintained for the whole
week of application, thus confirming the 7-day efficacy of action. The open follow-up phase demonstrated that therapeutic effects were maintained with prolonged therapy.
3.3. Safety and tolerability Local tolerability of the patches was good. In more than 90% of all assessed applications there was no or only a slight reaction. Severe skin reactions and pruritus were reported for just 1% of assessed applications of the active medication patch. According to the investigators’ judgement, during the placebo-controlled phase there were three cases of severe erythema in the active medication group and two in the placebo group. There was only one case of severe oedema in each group. During the follow-up phase, there was one additional case of erythema and oedema in each group. During the placebo-controlled phase, the proportion of patient bleedings, as assessed and recorded daily by the patient, was (as expected)
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higher in the active medication group when compared with placebo. However, most bleeding episodes were classified as regular, beginning between days 8 and 21 after the start of combination (estradiol/levonorgestrel) treatment and lasting for a mean duration of 4.609 3.99 days.
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No relevant changes in blood pressure were noted throughout the study in either group. Similarly, although there was a slight increase in body weight in both groups at the end of the study (B 2%), this was considered not to be clinically relevant. No clear trends for any of the safety
Fig. 3. Daily rates of hot flushes, (a) (day 1 – 3); and (b) (day 4 – 7).
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Fig. 4. Lipid patterns during the course of the study.
laboratory variables were seen. With regard to lipid pattern, there was no negative influence by the active treatment (Fig. 4). In addition, the active treatment with levonorgestrel did not show a negative effect on the high-density lipoprotein (HDL) cholesterol fraction. Treatment with the active medication patch was well tolerated. Only five serious adverse events were reported. These were bronchial asthma and biliary stones in the placebo group and a fracture of the femur, lumbalgia due to displacement of an invertebral disc, and suspected Me´ nie`re’s disease in the active medication group. None of these events were regarded as being causally related to the study medication. During the double blind, placebo-controlled phase, 29.9 and 22.0% of patients in the active medication and placebo groups, respectively, reported at least one adverse event. The difference was not statistically significant (P = 0.24). The only adverse events which occurred in \ 5% of patients within either treatment group were application site reactions (reported in 5.7% of patients
in the active group) and viral infections (reported in 5.5% of patients in the placebo group). Headache, often reported in association with the use of hormone replacement therapy, was reported in 1.1% of patients on active treatment and 2.2% of patients in the placebo group during the placebo-controlled phase. Other reactions commonly associated with the use of oral estrogen (e.g. nausea, vomiting, and abdominal pain) or oral progestogen (e.g. bloating and depression) were not specifically reported during the double blind, placebo-controlled phase of this study. However, gastrointestinal system disorders (including dyspepsia, gastrointestinal inflammation, epigastric pain, hypogastric pain, and dental pain) were reported by similar numbers of patients in both the active and placebo groups (4.5 and 4.4%, respectively).
3.4. Other assessments Patients assessed patch adhesiveness on a weekly basis. In total, the adhesiveness of 2586
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active medication patches was assessed throughout the study. Over this time period no detachment was reported for two-thirds of the medication patches. During the placebo-controlled phase, the investigator’s assessment of adhesiveness revealed adequate adhesiveness in 93.7% of patients in the active medication group. In addition, these results were confirmed during the open follow-up phase of the trial in which approximately 94% of patches were reported to have adequate adhesiveness. At the end of the study, subjective acceptance of the patches by the patients was generally good to very good (handling 81.7%, appearance 93.2% and convenience of use 82.4%) and the vast majority of patients (85.5%) were willing to consider continuing treatment. Data relating to patient compliance are presented in Tables 1 and 2. During both the double blind, placebo-controlled phase and the open follow-up phase, the proportion of patients who complied with the treatment regimen was above 90%. Patient compliance through the study was, therefore, good Tables 3 and 4.
4. Discussion The results of this study show that the use of the new 7-day transdermal sequential estradiol/ levonorgestrel patch regimen (Fem7®Combi) was well tolerated and superior to placebo in reducing symptoms in women with menopausal complaints. We used the Kupperman Index as a primary indicator of efficacy. Significant reductions in the
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score of patients receiving active treatment during both the double-blind, placebo-controlled phase and the open, uncontrolled follow-up phase (during which all patients received active treatment) showed that early treatment effects were maintained with prolonged therapy. Active therapy was also found to provide significant relief from hot flushes when compared with placebo during the double blind, placebo-controlled phase. No difference was observed between the first half of the week (days 1–3) and the second half of the week (days 4–7), demonstrating that the efficacy of Fem7® Combi was maintained throughout its 7-day application period. This sequential regimen is effective in reducing symptoms from week 2 of treatment onwards, and a statistical significance compared with placebo was reached from week four onwards, demonstrating a rapid onset of action in decreasing vasomotor symptoms. As anticipated from the results of similar studies investigating the benefits of hormone replacement therapy in menopausal women [28–30], reductions in the Kupperman Index score and the incidence of hot flushes were also apparent in patients receiving placebo during the placebo-controlled phase. However, reductions reported for placebo were smaller and stabilized earlier than those reported for active therapy, for which the magnitude of the reductions tended to increase over time. When patients receiving placebo switched to active therapy at the beginning of the follow-up phase, further improvements in symptoms were seen, with the magnitude of the benefit reaching that of patients who had received active therapy during both phases. This emphasizes the benefits of active therapy compared with placebo,
Table 2 Changes in the Kupperman Index from the end of the double-blind, placebo-controlled phase during the open follow-up ITT population Change in Kupperman index from the end of cycle 3, week 4 Medication (placebo-controlled/follow-up Cycle 4*, week 4 (absolute value) phase) Active/active (n = 71) −1.69 4.61 (7.4 9 5.73) Placebo/active (n = 76) −2.79 5.27 (11.9 9 8.08) * First cycle of the open, follow-up phase. ** Third cycle of the open, follow-up phase.
Cycle 6**, week 4 (absolute value) −2.89 5.32 (6.2 9 5.07) −6.49 6.97 (8.2 9 6.71)
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Table 3 Number of patients missing at least one application period during the double-blind, placebo-controlled phase-ITT population Active
Missing application period?
No Yes Total
but highlights the need to bear such placebo effects in mind when assessing the results of clinical studies of this type. Previous studies on sequential transdermal regimens for hormone replacement therapy have involved the use of either a combination patch that needs to be changed every 3– 4 days [31] or a 7-day estradiol patch plus oral progestogen [32,33]. The regimen used in this study is likely to be more convenient to use than these current alternatives and may, therefore, improve patient compliance. In this study, compliance was high (90%), and was similar to the rate reported in hysterectomized women receiving HRT in the form of a 7-day estrogen-only patch [34]. The acceptability of a regular bleed is reflected by the results of the present study, in which patient acceptance of the therapy was high, with over 85% of the women willing to consider continued use of the cyclic combined regimen. A fixed combination estradiol/progestogen patch may also provide a safer alternative to free combination therapy, including patch estradiol plus additional progestogen, since unopposed estrogen exposure may occur in subjects that fail to comply with the progestogen component of the regimen. Oral administration of progestogen generally requires the use of higher doses than those required with transdermal therapy, and this may result in a higher incidence of adverse effects [11]. When comparing our results with those of an earlier study using a 7-day-mono-estradiol patch (Fem7®; Merck KGaA; Germany) in hysterectomized women [34], the inclusion of levonorgestrel resulted in similar reductions in the Kupperman Index score as seen with estradiol alone. These findings suggest that the addition of
Placebo
N
%
N
%
79 5 84
94.5 6.0 100.0
84 4 88
95.5 4.5 100.0
progestogen had no influence on the beneficial effects of estrogen in reducing menopausal complaints. Overall, treatment with Fem7® Combi was well tolerated. No increase in blood pressure was reported in the active medication group and no unfavorable alterations in serum lipid profile were noted. This is in contrast to sequential combined HRT regimens where higher oral doses of levonorgestrel showed a negative effect on HDL cholesterol levels [35,36]. This new sequential combined transdermal HRT regimen with a very low dose of levonorgestrel (10 mg/day) did not negatively influence the HDL cholesterol fraction. Many women report weight gain around the time of the menopause and the use of hormone replacement therapy does not seem to either prevent or increase the early menopausal weight gain [37,38]. The local side effects of transdermal reservoir patches include skin irritation at the site of the application. However, newer formulations such as matrix patches cause fewer skin reactions than the original reservoir systems [39]. The matrix patches used in this study incorporated a novel patented matrix technology (SIS) which enables the hormones to penetrate the skin without the need for permeation enhancers and should minimize skin Table 4 Number of patients missing at least one application period during the open follow-up phase —ITT population Missing application period?
N
%
No Yes Total
145 3 148
98.0 2.0 100.0
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reactions. Indeed, local skin tolerability of the patches was reported to be good in this study. In more than 90% of all assessed application there was no or only a slight reaction. In conclusion, the new 7-day sequential estradiol/levonorgestrel combination patch (Fem7® Combi) is safe and effective for the treatment of menopausal complaints. No difference was observed between days 1– 3 and 4– 7, demonstrating that the efficacy of Fem7® Combi was maintained throughout its 7-day application period. A rapid relief of vasomotor symptoms was shown from week 2 of treatment, which reached statistical significance compared with placebo from week 4 onwards. The results reported in this study demonstrate that the use of levonorgestrel in such a low dose had no negative influence on the beneficial effects of estradiol on the lipid parameters. The subjective acceptance of Fem7® Combi by the patients was good to very good, and the vast majority of patients would consider continuing treatment. This new, unique, patent-protected SIS patch technology and the sequential combination of estradiol/levonorgestrel in a 7-day patch (Fem7® Combi) minimizes the potential side effects associated with the addition of an oral progestogen and may enhance compliance of the hormone replacement therapy for menopausal women.
Acknowledgements Principal investigator: T. Von Holst, Heidelberg, Germany; Clinical monitor: K. Hock, Merck KGaA Darmstadt, Germany; Clinical research associate: B. Gu¨ nther, Merck KGaA Darmstadt, Germany; Biometrics: M. Schlichting, Meck KGaA Darmstadt, Germany; Clinical centers (Germany): T. von Holst, Heidelberg; L. Hoppe, Schriesheim; H.-J. Paulski, Bammenthal; H.-D. Scheffzek, Heidelberg; L. Kiesel, Tu¨ bingen; H. Rohde-Werner, Eggenstein; R. Hussong, Villingen-Schwenningen; M.R. van Santen, Karlsruhe; S. Scho¨ nian, Rheinstetten; R. Schenkl, Ettlingen; J.-M. Klug, Rain/Lech; L. Ritter, Donauwo¨ rth; U. Kohoutek, Karlsruhe; P. Zimber, Gau-Algesheim; R. Landthaler, Krumbach;
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E. Seibicke, Bonn-Bad Godesberg; J. Repas, Schleiden; J. Herold, Mu¨ nchen; D. Tschu¨ rtz, Mu¨ nchen; B. Evers, Wo¨ rrstadt; K. Diegritz, Eberbach; R. Leblanc, Grevenbroich; G. Crass, Krefeld; G. Jacob, Mainz; Ch. Werner, Duidsburg; Th. Minack, Hamburg; C. Gru¨ newald, Bingen; W. Dolff, Essen; J. Klinghammer, Ko¨ ln; B. Schu¨ ssler, Neuss; W. Franken, Ko¨ ln; K. UrbanikFischer, Ko¨ ln.
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T. 6on Holst, B. Salbach / Maturitas 41 (2002) 231–242 parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73:275 –80. Kemp JF, Fryer JA, Baber RJ. An alternative regimen of hormone replacement therapy to improve patient compliance. Aust New Zealand J Obstet Gynaecol 1989;29:66 – 9. Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, Melis GB. Effects of low doses of transdermal 17b-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992;74:1396 – 400. Reaven GM. Role of insulin resistance in human disease. Banting lecture. Diabetes 1988;37:1595 – 607. Huppert LC. Hormonal replacement therapy: benefits, risks, doses. Med Clin North Am 1987;71:23 –39. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. New Engl J Med 1991;325:1196 –204. Mu¨ ck AO, Salbach B, Raabe T, von Holst T, Runnebaum W. Serum lipids in treatment with transdermal estradiol and oral norethisterone acetate. Geburtshilfe Frauenheilkunde 1995;55:393 –9. Hulka BS, Kaufman DG, Fowler WC, Grimson RC, Greenberg BG. Predominance of early endometrial cancers after long-term estrogen use. J Am Med Assoc 1980;244:2419 – 21. Brinton LA, Hoover RN. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol 1993;81:265 –71. Clisham PR, Cedars MI, Greendale G, Fu YS, Gambone J, Judd HL. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992;79:196 –201. Deligdisch L. Effects of hormone therapy on the endometrium. Modern Pathol 1993;6:91 –106. Persson I, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Br Med J 1989;298:147 –51. Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991;338:274 – 7. Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogen preparation by the postmenopausal and amenorrheal indices. J Clin Endocrinol 1953;13:688 –703. Draize JH, Woodard G, Calvery HO. Methods of the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 1994;82:377 –82.
[28] Good WR, John VA, Ramirex M, et al. Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Clin Ther 1996;18(6):1093 – 105. [29] Baachi-Modena A, Bolis P, Campagnoli C, et al. Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch. Maturitas 1997;27:285 – 92. [30] Studd J, Pornel B, Marton I, et al. Efficacy and acceptability of intranasal 17b-oestradiol for menopausal symptoms: randomised dose-response study. Lancet 1999;353:1574 – 8. [31] Whitehead MI, Fraser D, Schenkel L, Crook D. Transdermal administration of oestrogen/progesterone hormone replacement therapy. Lancet 1990;335:310 – 2. [32] Lutkie AWHM, Hackel S. Efficacy, tolerability and compliance of FemSeven, a once-weekly transdermal system, compared with Estraderm TTS 50. Eur J Clin Res 1997;9:111 – 22. [33] Lutkie AWHM, Hackel S, van de Ven LLM. Long-term tolerability and efficacy of Fem7®, a once-weekly transdermal system, in women with post-menopausal complaints. J Clin Res 1998;1:161 – 71. [34] Von Holst T, Salbach B. Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints. Maturitas 2000;34:143 – 53. [35] Graff-Iversen S, Stenvold I, und-Larsen PG, Nodarse LO, Tverdal A, Urdal P. Serum lipids in postmenopausal or perimenopausal women using estrogen alone, estrogen with levonorgestel, or estrogen with norethisterone, compared with non users. Results from a cross-sectional study in two Norwegian counties 1985 – 1988. J Clin Epidemiol 1998;51:1311 – 6. [36] Hirvonen E, Ma¨ lko¨ nen M, Manninen V. Effects of different progestogens on lipoproteins during postmenopausal replacement therapy. New Engl J Med 1981;304:560 – 3. [37] Reubinoff BE, Wurtman J, Rojansky N, Adler D, Stein P, Schenker JG, et al. Effects of hormone replacement therapy on weight, body composition, fat distribution and food intake in early postmenopausal women: a prospective study. Fertil Steril 1995;64(5):963 – 8. [38] Ongphiphadhanakul B, Chanprasertyothin S, Piaseu N, Chansirikanjana S, Puavilai G, Rajatanavin R. Change in body weight, after hormone replacement therapy in postmenopausal women is dependent on basal circulating leptin. Maturitas 1998;30(3):283 – 8. [39] Sturdee DW. Current hormone replacement therapy: what are the shortcomings? Advances in delivery. Int J Clin Pract 1999;53(6):468 – 72.
Efficacy of a new 7-day transdermal sequential estradiol/levonorgestrel patch in women Thomas von Holst *, Birgitt Salbach Uni6ersity Gynecological Clinic, Ruprecht-Karl Uni6ersity, Voßstrasse 9, D-69115 Heidelberg, Germany Received 15 May 2001; received in revised form 24 October 2001; accepted 6 November 2001
Abstract Objecti6e: To investigate the efficacy and tolerability of a new 7-day transdermal sequential estradiol/levonorgestrel patch (Fem7® Combi; Merck KGaA; Germany), versus placebo, as hormone replacement therapy in menopausal women. Methods: A multicentre, randomized, clinical study consisting of a 3-week screening phase, a 12-week double-blind, placebo-controlled treatment phase, and a 12-week open, follow-up phase. Women aged 40 – 65 years with an intact uterus and menopausal complaints were randomized to either 2 weeks of an estradiol mono patch (50 mg per 24 h) followed by 2 weeks of an estradiol/levonorgestrel combination patch (50 mg/10 mg per 24 h), or a placebo patch, for three 28-day cycles. Changes in the Kupperman Index and the frequency of hot flushes were assessed. Results: The sequential use of a 7-day estradiol patch and a 7-day estradiol/levonorgestrel patch was superior to placebo in reducing menopausal symptoms, and was well tolerated. At the end of the treatment phase, there was a statistically significant reduction in the Kupperman Index score versus placebo (P B 0.0001), and a statistically significant difference between groups in the proportion of patients with a reduction in the number of hot flushes (at least 50% versus baseline). During the open follow-up phase, there was a marked reduction in the Kupperman Index score and the number of hot flushes for patients switched from placebo to active study medication. The active medication was effective throughout the 1-week application period. Conclusions: The new 7-day transdermal sequential estradiol/levonorgestrel patch was well tolerated, providing rapid and effective relief of menopausal symptoms. The addition of low-dose levonorgestrel did not influence the beneficial effects of estradiol. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 7-Day-estradiol patch; 7-Day-estradiol/levonorgestrel patch; Transdermal sequential regimen; Estradiol; Levonorgestrel; Kupperman index; Hormone replacement therapy
1. Introduction Estrogen is an effective treatment for the climacteric symptoms and complaints associated * Corresponding author. Tel.: + 49-6221-567-856; fax: + 49-6221-565-713.
with menopause [1], of which vasomotor disorders (hot flushes) are the most frequent and particularly distressing. In recent years it has also become clear that estrogen can provide important additional health benefits by reducing cardiovascular morbidity and mortality [2,3] and preventing osteoporosis [4–10] in postmenopausal women.
0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 1 ) 0 0 2 9 7 - 3
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The transdermal administration of hormone replacement therapy has several advantages over oral administration. Oral estrogen undergoes substantial conversion to inactive metabolites in the gastrointestinal tract and substantial first-pass hepatic metabolism. Much lower doses of medication are effective with transdermal delivery because this inactivation and metabolism are avoided [11]. Patients receiving transdermal estrogen replacement therapy report fewer gastrointestinal adverse events (e.g. nausea, vomiting, abdominal pain), which may be directly related to the oral route [12] and also have a reduced risk of increased smooth muscle tone, gall bladder disease and venous thrombosis [13]. However, skin reactions (e.g. erythema and pruritus at the application site) might occur with transdermal delivery systems [14]. With the patch delivery, the risk of cardiovascular disease associated with insulin resistance is reduced compared with oral administration, as glucose metabolism is improved [15,16]. Transdermal delivery does not affect serum triglyceride levels, which are considered an independent risk factor for cardiovascular disease which may increase with oral estrogen therapy [17– 19]. Unopposed estrogen therapy is only used to treat women who have undergone a hysterectomy, because although estrogen minimizes the effects of menopausal symptoms, it stimulates the growth of endometrial tissue in the uterus and prolonged treatment is known to induce endometrial hyperplasia [20–22]. The addition of progestogen protects the endometrium from hyperplasia, effectively preventing endometrial cancer [23– 25]. Bleeding can be a reason for discontinuing hormone replacement therapy (HRT), especially since the bleeding can be unpredictable. The use of progestogen and estrogen together in a sequential treatment regimen should result in an acceptable bleeding pattern, which is an important consideration for continuation of therapy [11]. Combination therapy with estrogen and progestogen is, therefore, the most widely prescribed therapy for women who still have an intact uterus. There are, however, some concerns that the addition of progestogen may counteract the beneficial effects of estrogen on lipid
metabolism and in addition, cause premenstrual symptoms such as bloating, depression and headache [11], as well as other side effects. The objective of this clinical study was to investigate the efficacy and tolerability of the sequential use of two transdermal systems, a 7-day-estradiol patch and a 7-day-estradiol/ levonorgestrel patch (Fem7® Combi; Merck KGaA; Germany), compared with placebo, as cyclic hormonal replacement therapy in women with menopausal complaints. These patches only have to be changed every 7 days as opposed to every 3–4 days for other currently available patches. The unique patented matrix technology of the patches used in this study, which is based on styrene–isoprene–styrene (SIS) block copolymers, enables hormones to penetrate the skin without the need for permeation enhancers and thus reduces the likelihood of skin reactions, allowing the use of the lowest estradiol loading charge. This, combined with the 7-day application period, may offer the possibility of improved patient compliance compared with currently available sequential regimens.
2. Patients and methods
2.1. Study design This was a multicentre, randomized, clinical study consisting of an initial 3-week screening phase without study medication, followed by a 12-week double-blind, placebo-controlled phase, and a 12-week open follow-up phase during which all patients were treated with active medication. The placebo-controlled and follow-up phases were each divided into three 28-day (4-week) cycles. Patients were assessed prior to randomization, at entry into the study at 4, 12, 16, and 24 weeks, and at the end of the study.
2.2. Patients Women aged 40–65 years with an intact uterus and menopausal complaints were included in the study. Patients were in either a physiological postmenopausal state (last regular menstruation more
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than 12 months prior to inclusion in the study) or a surgical postmenopausal state (bilateral oophorectomy more than 3 months prior to inclusion in the study). Patients were required to have a normal gynaecological history and examination, serum estradiol (E2) levels less than 30 pg/ml, and follicle stimulating hormone (FSH) levels greater than 30 IU/l. Women who were randomized had experienced at least 15– 20 hot flushes per week within the month prior to screening and had an overall Kupperman Index score of \20 (the maximum possible Kupperman Index score is 51). Patients treated with oral sex hormones within the last 28 days, locally applied sex hormones within 21 days, or injectable sex hormones within 6 months prior to the start of the study were excluded from participating. The study was carried out in accordance with Good Clinical Practice and the Declaration of Helsinki as amended in Hong Kong (1989). All patients gave their written, informed consent to participate in the clinical study.
2.3. Medication Study medication consisted of the following: 7-day estradiol patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol per 24 h); 7-day estradiol/levonorgestrel patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol per 24 h; 1.5 mg levonorgestrel with a delivery rate of approximately, 10 mg levonorgestrel per 24 h); matching placebo monotherapy patch, or matching placebo combination therapy patch. No medication was administered during the initial screening phase, which was performed within the 3 weeks prior to randomization. During the double-blind, placebo-controlled phase, the following medication was administered during each of the three 28-day cycles: either the 7-day estradiol patch for 2 weeks followed by the 7-day estradiol/levonorgestrel patch for 2 weeks, or the placebo monotherapy patch for 2 weeks followed by the placebo combination therapy patch for 2 weeks. During the open follow-up phase, all patients received active drug therapy (the 7-day estradiol patch for 2 weeks followed by the 7-day
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estradiol/levonorgestrel patch for 2 weeks) for a further 12 weeks (three 28-day cycles). The patches used in this study comprised a thin, flexible, transparent film in an octagonal shape approximately 15 cm2 in size. The release liner comprised a thicker, less flexible transparent film, square in shape with a punched cut to assist removal. The unique patented matrix technology of these patches, which is based on SIS block copolymers, allows estradiol to penetrate the skin without the need for permeation enhancers.
2.4. Efficacy 6ariables Patients reported the presence and severity of menopausal symptoms for the interval between visits by means of the Kupperman Index [26]. Patients used diary cards to report the daily frequency of hot flushes. The primary efficacy variable in the present study was the change from baseline in the Kupperman Index score at the end of the placebo-controlled phase (following 12 weeks of treatment). Secondary efficacy variables included the change from baseline in the Kupperman Index score for cycles 1, 3, 4, and 6, and at study endpoint, the number of hot flushes per week (days 1–3 and days 4–7) compared with baseline values and the number of patients with a greater than 50% reduction in the number of hot flushes per week.
2.5. Safety assessments Skin tolerability was assessed by the investigator on the basis of two 5-point scales (one for erythema and one for oedema), using a modified assessment system [27]. The occurrence of skin reactions e.g. redness/swelling or itchiness at the site of patch application was also recorded by the patient at the end of each application period and the incidence of skin reactions was assessed against the number of patches applied. Patients underwent a gynaecological examination (vagina, mammae and cytological smear) at both the start of and end of the study. Endometrial height was sonographically determined at the beginning of the study, at the end of the treatment phase and at the end of the study.
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Haematology, biochemistry, and serum lipid profile samples were assessed in fasting condition before enrolment, and after 3 (lipid profile only) and 6 cycles of therapy. All adverse events were recorded whether reported by the patient or observed by the investigator, including haematology and serum biochemistry data, irrespective of any causal relationship with the study drugs.
2.6. Other assessments Patch adhesiveness was assessed by the investigator at weeks 4, 12, 16, and 24, and rated as clinically adequate (degree of detachment 5 40%) or clinically inadequate (degree of detachment \ 40%). The patient also assessed adhesiveness on a weekly basis at the end of each application period. Handling, appearance and convenience of the patch were rated by the patient as very good, good, moderate, or poor at the end of cycle 2 and at the end of the study. In addition, patients were requested to indicate whether they would continue using the patch after the study. Counting the unused medication returned by the patients assessed compliance with medication.
2.7. Statistical methods For continuous data, treatment groups were compared using the two-tailed Wilcoxon ranksum test. To allow for a meaningful clinical interpretation of results, differences between groups were based on a one-way analysis of variance. Response rates were analyzed by means of Fisher’s Exact test. All statistical tests were two-sided with a 5% significance level. The intention-to-treat (ITT) population was used to analyze efficacy data during the double blind, placebo-controlled phase of the study. Patients qualified for the ITT population if they had been treated with the study medication at least once and had provided any follow-up data for one or more target efficacy variables. In this context, missing values were replaced using LOCF (last observation carried forward) methodology.
3. Results
3.1. Subjects A total of 216 patients from 33 centers were enrolled. Thirty-seven patients withdrew prior to randomization— most did not meet the inclusion criteria (particularly with regard to baseline hormone concentrations). A total of 179 women (n = 87, active therapy; n= 92, placebo therapy) were then randomized to the double-blind treatment phase. Estradiol and follicle stimulating hormone levels during randomization were comparable between the treatment groups. Both groups were well matched in terms of demographic data and baseline values for the Kupperman Index and in terms of complaint scores regarding the urogenital system, whereas the weekly number of hot flushes was higher at baseline in the active medication group. Mean age was 53.5 and 53.1 years in the active medication and placebo groups, respectively. In total, 31 patients withdrew from the study during the placebo-controlled phase (15 in the active treatment group and 16 in the placebo group), eight of whom were withdrawn due to adverse events, which was the most frequent reason for patient withdrawal. A total of 149 patients, therefore, entered the open follow-up phase (72 patients who remained on active treatment and 76 patients who were switched from placebo to active medication).
3.2. Efficacy Mean baseline values for the Kupperman Index were similar in the two treatment groups (mean values were 26.3 in the active medication group and 27.1 in the placebo group) and indicated moderate-to-severe climacteric complaints; individual values were as high as 44 in the active medication group and 41 in the placebo group. In both groups, reductions in the Kupperman Index score versus baseline were observed throughout the placebo-controlled phase, although these reductions were the greatest in the group receiving active therapy (Fig. 1).
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Fig. 1. Mean values of Kupperman Index for the new 7-day transdermal sequential system: a 7-day-estradiol patch and a 7-day-estradiol/levonorgestrel patch, and placebo over three cycles (Phase II, placebo-controlled phase).
The difference between treatment groups for the primary efficacy variable (change in Kupperman Index score at the end of the placebo-controlled phase versus baseline) was statistically significant in favor of the active medication group (P= 0.0001), with the mean value of the Kupperman Index score declining from 26.3 to 9.5 in the active treatment group and from 27.1 to 15.9 in the placebo group. The mean difference between groups concerning changes in Kupperman Index score at the end of the placebo-controlled phase versus baseline was 5.6 (95% CI 3.08– 8.13). The open follow-up phase showed that early treatment effects were maintained with prolonged active therapy (Table 1). A marked reduction in the Kupperman Index score was observed when placebo patients were switched to active medication during the follow-up phase (Table 1). At the end of this phase, the Kupperman Index scores were significantly reduced (P B0.01), irrespective of whether patients received placebo or active medication during the placebo-controlled phase. Unlike the Kupperman Index scores, the mean weekly number of hot flushes at baseline was higher in the active medication group compared with the placebo group (49.4 vs. 40.0). However, a distinctive difference in the reduction of hot
flushes from baseline between the active medication and placebo recipients was noted from week 2 of treatment throughout the placebo-controlled phase, with differences being significant in favor of the active treatment at weeks 4, 8, and 12 (Fig. 2), confirming the rapid onset of action of Fem7® Combi. Table 1 Demographic data — ITT population Active (n =84) Age (mean 9 SD; years) Height (mean 9SD; cm) Weight (mean 9 SD; kg) Non-smokers (patients) Kuppermann index (mean 9SD) Urogenital system complaint score (mean 9SD) Weekly hot flushes (mean 9SD; patients)
Placebo (n = 88)
53.5 94.83
53.1 95.35*
164.2 95.70
163.3 9 6.20
66.18 98.740
66.81 9 9.737*
55 (65.5%)
60 (68.22%)*
26.3 95.21
27.1 95.10
2.4 91.84
2.6 91.99
49.4 945.14**
*P=NS; **n= 74; †n =78.
40.0 921.62†
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Fig. 2. Weekly frequency of hot flushes for the new 7-day transdermal sequential system, a 7-day-estradiol patch, and a 7-day-estradiol/levonorgestrel patch versus placebo over 12 weeks. Between-group comparisons: Pweek4 =0.0003; Pweek8 =0.0001; Pweek12 =0.0002 (Phase II, placebo-controlled phase).
The difference between the groups at the end of the placebo-controlled phase with regard to changes from baseline was estimated to be 21.47 hot flushes per week (95% CI 10.56– 32.38), again showing a significant difference between treatments in favor of the active medication group. At the end of the open follow-up phase, the mean number of hot flushes was shown to be further reduced to 5.1 per week in the group who received active medication throughout the study, and 5.5 per week in the group who switched from placebo to active therapy at the beginning of the follow-up phase. Considerably more patients on active medication compared with placebo experienced a clinically relevant and statistically significant reduction in the number of hot flushes by at least 50% compared with baseline in the placebo-controlled phase of the study (81.16% reduction versus 57.33%; P= 0.0023). By separating the results for days 1–3 (Fig. 3a) and 4– 7 (Fig. 3b) of treatment with active medication, it was further shown that efficacy, in terms of the frequency of hot flushes, could be maintained for the whole
week of application, thus confirming the 7-day efficacy of action. The open follow-up phase demonstrated that therapeutic effects were maintained with prolonged therapy.
3.3. Safety and tolerability Local tolerability of the patches was good. In more than 90% of all assessed applications there was no or only a slight reaction. Severe skin reactions and pruritus were reported for just 1% of assessed applications of the active medication patch. According to the investigators’ judgement, during the placebo-controlled phase there were three cases of severe erythema in the active medication group and two in the placebo group. There was only one case of severe oedema in each group. During the follow-up phase, there was one additional case of erythema and oedema in each group. During the placebo-controlled phase, the proportion of patient bleedings, as assessed and recorded daily by the patient, was (as expected)
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higher in the active medication group when compared with placebo. However, most bleeding episodes were classified as regular, beginning between days 8 and 21 after the start of combination (estradiol/levonorgestrel) treatment and lasting for a mean duration of 4.609 3.99 days.
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No relevant changes in blood pressure were noted throughout the study in either group. Similarly, although there was a slight increase in body weight in both groups at the end of the study (B 2%), this was considered not to be clinically relevant. No clear trends for any of the safety
Fig. 3. Daily rates of hot flushes, (a) (day 1 – 3); and (b) (day 4 – 7).
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Fig. 4. Lipid patterns during the course of the study.
laboratory variables were seen. With regard to lipid pattern, there was no negative influence by the active treatment (Fig. 4). In addition, the active treatment with levonorgestrel did not show a negative effect on the high-density lipoprotein (HDL) cholesterol fraction. Treatment with the active medication patch was well tolerated. Only five serious adverse events were reported. These were bronchial asthma and biliary stones in the placebo group and a fracture of the femur, lumbalgia due to displacement of an invertebral disc, and suspected Me´ nie`re’s disease in the active medication group. None of these events were regarded as being causally related to the study medication. During the double blind, placebo-controlled phase, 29.9 and 22.0% of patients in the active medication and placebo groups, respectively, reported at least one adverse event. The difference was not statistically significant (P = 0.24). The only adverse events which occurred in \ 5% of patients within either treatment group were application site reactions (reported in 5.7% of patients
in the active group) and viral infections (reported in 5.5% of patients in the placebo group). Headache, often reported in association with the use of hormone replacement therapy, was reported in 1.1% of patients on active treatment and 2.2% of patients in the placebo group during the placebo-controlled phase. Other reactions commonly associated with the use of oral estrogen (e.g. nausea, vomiting, and abdominal pain) or oral progestogen (e.g. bloating and depression) were not specifically reported during the double blind, placebo-controlled phase of this study. However, gastrointestinal system disorders (including dyspepsia, gastrointestinal inflammation, epigastric pain, hypogastric pain, and dental pain) were reported by similar numbers of patients in both the active and placebo groups (4.5 and 4.4%, respectively).
3.4. Other assessments Patients assessed patch adhesiveness on a weekly basis. In total, the adhesiveness of 2586
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active medication patches was assessed throughout the study. Over this time period no detachment was reported for two-thirds of the medication patches. During the placebo-controlled phase, the investigator’s assessment of adhesiveness revealed adequate adhesiveness in 93.7% of patients in the active medication group. In addition, these results were confirmed during the open follow-up phase of the trial in which approximately 94% of patches were reported to have adequate adhesiveness. At the end of the study, subjective acceptance of the patches by the patients was generally good to very good (handling 81.7%, appearance 93.2% and convenience of use 82.4%) and the vast majority of patients (85.5%) were willing to consider continuing treatment. Data relating to patient compliance are presented in Tables 1 and 2. During both the double blind, placebo-controlled phase and the open follow-up phase, the proportion of patients who complied with the treatment regimen was above 90%. Patient compliance through the study was, therefore, good Tables 3 and 4.
4. Discussion The results of this study show that the use of the new 7-day transdermal sequential estradiol/ levonorgestrel patch regimen (Fem7®Combi) was well tolerated and superior to placebo in reducing symptoms in women with menopausal complaints. We used the Kupperman Index as a primary indicator of efficacy. Significant reductions in the
239
score of patients receiving active treatment during both the double-blind, placebo-controlled phase and the open, uncontrolled follow-up phase (during which all patients received active treatment) showed that early treatment effects were maintained with prolonged therapy. Active therapy was also found to provide significant relief from hot flushes when compared with placebo during the double blind, placebo-controlled phase. No difference was observed between the first half of the week (days 1–3) and the second half of the week (days 4–7), demonstrating that the efficacy of Fem7® Combi was maintained throughout its 7-day application period. This sequential regimen is effective in reducing symptoms from week 2 of treatment onwards, and a statistical significance compared with placebo was reached from week four onwards, demonstrating a rapid onset of action in decreasing vasomotor symptoms. As anticipated from the results of similar studies investigating the benefits of hormone replacement therapy in menopausal women [28–30], reductions in the Kupperman Index score and the incidence of hot flushes were also apparent in patients receiving placebo during the placebo-controlled phase. However, reductions reported for placebo were smaller and stabilized earlier than those reported for active therapy, for which the magnitude of the reductions tended to increase over time. When patients receiving placebo switched to active therapy at the beginning of the follow-up phase, further improvements in symptoms were seen, with the magnitude of the benefit reaching that of patients who had received active therapy during both phases. This emphasizes the benefits of active therapy compared with placebo,
Table 2 Changes in the Kupperman Index from the end of the double-blind, placebo-controlled phase during the open follow-up ITT population Change in Kupperman index from the end of cycle 3, week 4 Medication (placebo-controlled/follow-up Cycle 4*, week 4 (absolute value) phase) Active/active (n = 71) −1.69 4.61 (7.4 9 5.73) Placebo/active (n = 76) −2.79 5.27 (11.9 9 8.08) * First cycle of the open, follow-up phase. ** Third cycle of the open, follow-up phase.
Cycle 6**, week 4 (absolute value) −2.89 5.32 (6.2 9 5.07) −6.49 6.97 (8.2 9 6.71)
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Table 3 Number of patients missing at least one application period during the double-blind, placebo-controlled phase-ITT population Active
Missing application period?
No Yes Total
but highlights the need to bear such placebo effects in mind when assessing the results of clinical studies of this type. Previous studies on sequential transdermal regimens for hormone replacement therapy have involved the use of either a combination patch that needs to be changed every 3– 4 days [31] or a 7-day estradiol patch plus oral progestogen [32,33]. The regimen used in this study is likely to be more convenient to use than these current alternatives and may, therefore, improve patient compliance. In this study, compliance was high (90%), and was similar to the rate reported in hysterectomized women receiving HRT in the form of a 7-day estrogen-only patch [34]. The acceptability of a regular bleed is reflected by the results of the present study, in which patient acceptance of the therapy was high, with over 85% of the women willing to consider continued use of the cyclic combined regimen. A fixed combination estradiol/progestogen patch may also provide a safer alternative to free combination therapy, including patch estradiol plus additional progestogen, since unopposed estrogen exposure may occur in subjects that fail to comply with the progestogen component of the regimen. Oral administration of progestogen generally requires the use of higher doses than those required with transdermal therapy, and this may result in a higher incidence of adverse effects [11]. When comparing our results with those of an earlier study using a 7-day-mono-estradiol patch (Fem7®; Merck KGaA; Germany) in hysterectomized women [34], the inclusion of levonorgestrel resulted in similar reductions in the Kupperman Index score as seen with estradiol alone. These findings suggest that the addition of
Placebo
N
%
N
%
79 5 84
94.5 6.0 100.0
84 4 88
95.5 4.5 100.0
progestogen had no influence on the beneficial effects of estrogen in reducing menopausal complaints. Overall, treatment with Fem7® Combi was well tolerated. No increase in blood pressure was reported in the active medication group and no unfavorable alterations in serum lipid profile were noted. This is in contrast to sequential combined HRT regimens where higher oral doses of levonorgestrel showed a negative effect on HDL cholesterol levels [35,36]. This new sequential combined transdermal HRT regimen with a very low dose of levonorgestrel (10 mg/day) did not negatively influence the HDL cholesterol fraction. Many women report weight gain around the time of the menopause and the use of hormone replacement therapy does not seem to either prevent or increase the early menopausal weight gain [37,38]. The local side effects of transdermal reservoir patches include skin irritation at the site of the application. However, newer formulations such as matrix patches cause fewer skin reactions than the original reservoir systems [39]. The matrix patches used in this study incorporated a novel patented matrix technology (SIS) which enables the hormones to penetrate the skin without the need for permeation enhancers and should minimize skin Table 4 Number of patients missing at least one application period during the open follow-up phase —ITT population Missing application period?
N
%
No Yes Total
145 3 148
98.0 2.0 100.0
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reactions. Indeed, local skin tolerability of the patches was reported to be good in this study. In more than 90% of all assessed application there was no or only a slight reaction. In conclusion, the new 7-day sequential estradiol/levonorgestrel combination patch (Fem7® Combi) is safe and effective for the treatment of menopausal complaints. No difference was observed between days 1– 3 and 4– 7, demonstrating that the efficacy of Fem7® Combi was maintained throughout its 7-day application period. A rapid relief of vasomotor symptoms was shown from week 2 of treatment, which reached statistical significance compared with placebo from week 4 onwards. The results reported in this study demonstrate that the use of levonorgestrel in such a low dose had no negative influence on the beneficial effects of estradiol on the lipid parameters. The subjective acceptance of Fem7® Combi by the patients was good to very good, and the vast majority of patients would consider continuing treatment. This new, unique, patent-protected SIS patch technology and the sequential combination of estradiol/levonorgestrel in a 7-day patch (Fem7® Combi) minimizes the potential side effects associated with the addition of an oral progestogen and may enhance compliance of the hormone replacement therapy for menopausal women.
Acknowledgements Principal investigator: T. Von Holst, Heidelberg, Germany; Clinical monitor: K. Hock, Merck KGaA Darmstadt, Germany; Clinical research associate: B. Gu¨ nther, Merck KGaA Darmstadt, Germany; Biometrics: M. Schlichting, Meck KGaA Darmstadt, Germany; Clinical centers (Germany): T. von Holst, Heidelberg; L. Hoppe, Schriesheim; H.-J. Paulski, Bammenthal; H.-D. Scheffzek, Heidelberg; L. Kiesel, Tu¨ bingen; H. Rohde-Werner, Eggenstein; R. Hussong, Villingen-Schwenningen; M.R. van Santen, Karlsruhe; S. Scho¨ nian, Rheinstetten; R. Schenkl, Ettlingen; J.-M. Klug, Rain/Lech; L. Ritter, Donauwo¨ rth; U. Kohoutek, Karlsruhe; P. Zimber, Gau-Algesheim; R. Landthaler, Krumbach;
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E. Seibicke, Bonn-Bad Godesberg; J. Repas, Schleiden; J. Herold, Mu¨ nchen; D. Tschu¨ rtz, Mu¨ nchen; B. Evers, Wo¨ rrstadt; K. Diegritz, Eberbach; R. Leblanc, Grevenbroich; G. Crass, Krefeld; G. Jacob, Mainz; Ch. Werner, Duidsburg; Th. Minack, Hamburg; C. Gru¨ newald, Bingen; W. Dolff, Essen; J. Klinghammer, Ko¨ ln; B. Schu¨ ssler, Neuss; W. Franken, Ko¨ ln; K. UrbanikFischer, Ko¨ ln.
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