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The long-term tolerability and efficacy of OESCLIM®: results of a 1-year study
Maturitas 33 (1999) S73 – S81 www.elsevier.com/locate/maturitas
The long-term tolerability and efficacy of OESCLIM®: results of a 1-year study R. Taurelle a,*, M. L’Hermite b, W. Haenggi c, C. Lauritzen d, J.W. Studd e a
Ser6ice Gynicologie, Hoˆpital Bouciaut, 78 Rue de la Con6ention, 75730 Paris Cedex 15, France b Hoˆpital Brugmann, Brussels, Belgium c Uni6ersitats-Frauenklinik und Kantonales Frauenspital, Bern, Switzerland d Ulm, Germany e Lister Hospital, London, UK
Abstract Objecti6es: A 1-year, open-label, non-comparative study evaluated the long-term tolerability and acceptability of a new generation matrix patch in post menopausal women with estrogen deficiency. Methods: Menopausal women (224) from 37 centres in five European countries received OESCLIM® 50 mg/d (17-b estradiol) for 3 months, titrated if necessary to either 25 or 100 mg/d for a further 9 months. Patients received either a continuous or discontinuous estradiol regimen with concomitant sequential progestogen (except hysterectomised patients). Skin tolerability was assessed by patient diaries and questionnaires. Global tolerability, efficacy, laboratory parameters and global acceptability were also monitored. Results: Almost two-thirds of women did not experience any kind of skin reaction and only 4.3% of all applications (752/17 702) caused site reactions. Of these, the majority caused only slight or no discomfort (63.2%). Only 0.37% of total applications required patch removal; none required therapy. A low percentage of patients withdrew due to tolerability issues: 2.7% due to skin reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after 2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no increase in triglyceride levels. Investigators assessed treatment as effective in 96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in 89.5%. At the end of this 1 year study, 79% of patients wished to continue therapy. Conclusion: OESCLIM® is well tolerated locally and systemically in long-term therapy with a high proportion of patients wishing to continue therapy after 1 year. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Transdermal; Estradiol; OESCLIM®; HRT; Tolerability; Compliance
1. Introduction and aims The menopause is a period of great physiological change in a woman’s life. The ovaries begin to
* Corresponding author.
fail in their production of sex hormones and estrogen levels gradually decrease over a number of years. Estrogen deficiency may result in symptoms which can be at best a nuisance, and at worse, debilitating and it is estimated that 85% of women will suffer from some kind of vasomotor symptom during this time [1].
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Hormone replacement therapy (HRT) and in particular, estrogen therapy was developed as long ago as the 1940s to relieve these symptoms. Since then, there have been many innovations and advances which have allowed HRT to become one of the most effective prophylactic treatments that physicians can prescribe for their patients. Despite the many benefits associated with HRT, compliance with HRT is still low. One of the reasons women discontinue therapy is possible side effects resulting from poor tolerability of existing HRT products. OESCLIM® (or ESCLIM® or ESCLIMA®) is an innovative new transdermal HRT product delivering 17-b estradiol for the relief of menopausal symptoms. Its non-acrylic foam backing makes it unique among transdermal patches as it is extensible and flexible, making it more comfortable for patients to wear. Pharmacokinetic studies have shown OESCLIM® to provide an improved pharmacokinetic profile compared to other transdermal systems including Estraderm TTS® 50 [2], Menorest®/Vivelle® [3] and Systen® [4]. It has also been shown to have improved adhesivity and local tolerability in a comparative study with Estraderm TTS® 50 [5]. The aim of this study was to evaluate the long-term tolerability of OESCLIM® in treating post menopausal women with estrogen deficiency and to assess patients’ response to long-term therapy.
2. Methods The study was a well-designed, open-label, noncomparative clinical study conducted in 37 centres in five European countries (UK, France, Germany, Belgium, Switzerland). The study received ethics committee approval according to the legislation of each country, and was conducted to Good Clinical Practice standards.
2.1. Patient selection Caucasian women attending the study clinics were selected for the study if they fulfilled a number of selection criteria (see Table 1). Patients
who had previously received treatments other than transdermal estrogen were eligible after a one month wash-out period. If women had undergone an oophorectomy, they were also eligible for inclusion 1 month after the operation. After a screening visit to assess eligibility, patients who gave informed consent to participate returned to the clinic to begin therapy (day 0). A further three visits were required between days 8 and 15 of months 3, 7 and 12. A final interview was conducted during the first week of month 13.
2.2. Treatment groups All patients were treated, for the first 3 months of study, with OESCLIM® 50 delivering 50 mg/d of 17-b estradiol. If required after this time, the dose was titrated to either 25mg/d or 100mg/d, according to response and tolerability. Patients were given either a continuous or a discontinuous estradiol regimen at the discretion of the investigator. Discontinuous regimens comprised 24–28 days of estrogen treatment followed by a treatment-free period of between 2 and 7 days. OESCLIM® was applied to the buttocks twice weekly (one for 3 days; then a second patch for 4 days). Alternate buttocks were used to vary the application site. In line with prescribing information, the skin was to be clean, dry, healthy and not treated with creams or lotions before application. Patients who had not undergone a hysterectomy, were also prescribed an oral, concomitant progestogen to prevent endometrial hyperplasia. This was administered sequentially for 12–16 days at the end of the estrogen therapy. DyTable 1 Patient selection criteria Post menopausal women suffering symptoms of estrogen deficiency through either a natural or surgical menopause Estradiol and FSH plasma levels within postmenopausal range No history of chronic skin disease or cutaneous contact allergy No contraindication for estrogen therapy Not on concomitant treatments likely to influence the results of the study
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drogesterone was the only non-androgenic progestogen available in all European countries involved in the study, but other progestogens could be chosen from an approved list.
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asthenia and mood. At the screening and final clinical visits, vaginal smears were taken for the assessment of vaginal trophicity. The investigator also clinically assessed vulval trophicity and cervical mucus.
2.3. Measurements 2.3.1. Tolerability 2.3.1.1. Patient diaries. Patients were asked to record details of any skin reactions. These included the date of patch application and removal; site and duration of reaction; type of reaction; degree of discomfort and whether the reaction required the patch to be removed. The degree of discomfort and type of each reaction were assessed using pre-defined headings (no discomfort, slight discomfort, discomfort, considerable discomfort and redness, spots, swelling, itching, or burning sensation). Patients were also assessed at clinic visits and details of any corrective treatments noted. Isolated erythema which lasted B 1 h after removal of the patch were not included. General tolerability was assessed in addition to local skin tolerability. Patients were asked to record signs of hyperestrogenism (menorrhagia, mastodynia, nausea, abdominal pain and bloating, heavy legs, and oedema). Any adverse events including withdrawal bleeding or vaginal bleeding were also noted, along with information on the abundance and duration of bleeds. During clinical examinations, data were collected on a number of physiological parameters including blood pressure, heart rate, body weight and laboratory tests were conducted to assess changes in estradiol levels and lipid profiles. Blood samples were taken outside of sequence of concomitant progestogen. 2.3.2. Efficacy assessments The study was not designed to demonstrate the efficacy of OESCLIM®; however, efficacy parameters were assessed by recording the number of vasomotor symptoms (hot flushes and night sweats) experienced at baseline and at each visit. Hot flushes were graded according to severity. Seven other symptoms were recorded including urinary incontinence, vaginal dryness, libido disorders, osteoarticular pain, quality of sleep,
2.3.3. Patient satisfaction At the end of the study period, the investigator qualitatively assessed general and local tolerability for each patient. Patients were asked to assess their general condition and feeling of well-being, general tolerability and satisfaction with treatment. They were also asked whether they would like to continue treatment or not. 2.4. Statistical analysis Statistical analyses used mainly descriptive and qualitative methods. Inferential methods were used only for variables relating to local tolerability and biological parameters. For local tolerability, 95% confidence intervals were calculated and for biological values, changes from baseline to endpoint were analysed at the 10% significance level.
3. Results
3.1. Patient characteristics Of 305 patients selected, 224 were eligible for inclusion in the study, with an age range from 39 to 72 years. As expected, there was an age range difference between the women who had undergone a natural menopause, and those who had undergone a surgical menopause, where there was a higher proportion of patients under the age of 45 years. The baseline characteristics of the patients included in the study are recorded in Table 2. Of the natural menopause patients, 70 patients (40%) received a continuous regimen, and 107 (60%) received a discontinuous regimen. The split was more uneven in the women who had undergone a surgical menopause because of the high number allocated to receive a continuous regimen, 38 (81%). Only nine patients (19%) with surgical
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Table 2 Patient characteristics at baseline, by type of menopausea Characteristics
Natural menopause n = 177
Surgical menopause n =47
All patients n = 224
Age (years) Age at onset of menopause Time since menopause (years) Hot flushes per day
52.7 48.9 3.9 3.9
52.6 46.4 6.2 4.5
52.7 48.3 4.5 4.0
(95.6) (9 3.6) (9 4.9) (94.0)
(97.2) (9 7.4) ( 9 7.2) (95.6)
( 9 5.9) ( 94.8) (9 5.6) ( 94.4)
a
Mean9 SD. Data on the ‘age at onset of menopause’ and the ‘time since menopause’ was unavailable in 19 natural menopause patients.
menopause were given a discontinuous regimen. Overall, however, the split between the two groups was comparable: 108 patients (48%) received a continuous regimen and 116 (52%) received discontinuous therapy.
3.1.1. Vasomotor symptoms At baseline, 85.5% of patients were found to be suffering from vasomotor symptoms, with a mean number of four hot flushes per day. The number of hot flushes experienced by patients per day ranged from 0 to 30, with patients in the surgical menopause group having a higher mean number of flushes per day than those who had undergone a natural menopause. In relation to night sweats, there were no important differences between the two groups. However, 27.2% of patients experienced very frequent night sweats; 27.2% frequently; 15.2% had them rarely, and 30.4% of patients had no night sweats at all. 3.2. Patient participation and withdrawal One hundred and seventy-five patients completed the study (78%) according to the study protocol. Forty-nine patients withdrew or were withdrawn from the study during the 12-month period. Of these, only 34 (15.1%) withdrew due to adverse events. Other reasons for withdrawal included: five patients who withdrew consent; two patients were lost to follow-up; six were ineligible after re-assessment; two withdrew for other reasons. The main adverse events leading to withdrawal were signs of hyperestrogenism (17 patients) and application site reactions (six patients).
3.2.1. Dose titration All patients were placed on the 50 mg/d dose for the first 3 months of the study. After that time, nearly a quarter of the patients (51 patients, 22.8%) were titrated to a lower dose of 25 mg/day. This was mainly due to symptoms of hyperestrogenism, but this group were effectively maintained on the low dose for the remainder of the study. Twelve patients (5.4%) needed the dose to be titrated upwards to 100 mg/day, due to lack of efficacy. Only five patients changed dose more than once during the study, and the remaining 156 patients (69.6%) remained on the 50 mg/d dose they had started on. 3.3. Local skin tolerability Skin tolerability data was available for 222 patients who applied a total of 17 702 patches over the course of the study. Only 4.3% of all applications (752/17 702) caused site reactions, almost two-thirds of the women did not experience any kind of skin reaction, and for the majority of those who did have a reaction, this occurred with only 1–10% of the patches they used, as shown in Fig. 1 (distribution of the percentage of applications per patient which caused a site reaction). The mean number of local reactions were similar in each of the treatment regimens. The women on discontinuous therapy had 3.0 reactions per patient (mean), whereas the patients in the continuous therapy group had 3.8 reactions per patient over the year. The type of skin reaction experienced is shown in Table 3. The pattern of site reactions was of the same magnitude across each dosage and for the different regimens. The continuous regimen group
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Fig. 1. Percentage of total applications per patient which caused reactions.
had 402/9073 reactions (4.4%) and there were 350/8629 reactions (4.1%) in the discontinuous group. Redness and itching often occurred together and were the most common types of reaction noted. The majority of reactions (68%) occurred during the first 6 months of treatment. The median duration of reaction was only 12 h. Of the reactions experienced, the majority caused only slight or no discomfort (63.2%) and only 8.8% of total reactions required the patch to be removed. This represented only 0.37% of the total applications over the entire study period and none of these required any corrective therapy. The six patients who withdrew prematurely because of site reactions were all receiving the 50 mg/d dose, split equally between the discontinuous and continuous regimens.
3.4. Global tolerability Global tolerability with OESCLIM® was good with only 17 patients (7.5%) having to withdraw
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from the study due to signs of hyperestrogenism. A total of 138 patients (61.6%) experienced at least one adverse event attributed to HRT, with hyperestrogenism and breakthrough bleeding/ spotting being the most common symptoms. However, 36.6% of patients experienced hyperestrogenic adverse events and of these patients, during the first 3 months of HRT, 24.1% experienced adverse events coded as ‘altered hormone levels’. This decreased to 7.6% of patients during the following 3 months and then fell to B 5% for the rest of the study duration. The most frequent hyperestrogenic symptoms recorded were breast pain (68 patients; 30.4%), weight gain (14 patients; 6.3%) and menorrhagia (12 patients; 5.4%). Apart from adverse events related to bleeding, there were not clinically important differences between the natural and surgical menopause groups. The total study group included 141 patients who had not undergone a complete hysterectomy, and almost 97% had at least one episode of withdrawal bleeding over the year. However, this was an expected event as progestogen was given sequentially for these patients. The average duration of bleeding was 4.3 days per month, but higher doses and a continuous regimen led to more abundant bleeds. Breakthrough bleeding was only induced in 14.1% of the monthly cycles assessed, and the majority of these (67.9%) were due to spotting. Other adverse events included symptoms related to urogenital system (34 patients; 15.2%); ‘body as a whole’ (30 patients; 13.4%) and ‘metabolic’ or nutritional disorders (19 patients; 8.5%). These did not appear to be related to dose or menopause-type.
Table 3 Types of application site reaction at each dosea Type of reaction
25 mg/d, r = 134b
50 mg/d, r = 607b
Redness Itching Spots Burning sensation Swelling
69 104 24 30 6
484 354 141 100 53
a b
100 mg/d, r = 11b 4 10 1 0 1
Total for all dosages, r =752b 557 468 166 130 60
(3.1%) (2.6%) (0.9%) (0.7%) (0.3%)
Number (% of total applications). Data on type of reaction missing in four cases. r= number of reactions. Reactions could be categorised as more than one type.
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Fig. 2. Percentage of patients reporting other symptoms at baseline (Vi) and after 11 months treatment (V3).
There was a slight trend towards weight gain in the study, but this was low ( + 0.8 kg) and there was a wide range of weight change. Most of the mean weight gain appeared very early in the study (by the end of month 3) and mean weight stabilised thereafter with only minor fluctuations. Monitoring of other vital signs revealed that there were slight decreases in both mean blood pressure and pulse from baseline to end point. Systolic pressure decreased by 0.9 mmHg, and diastolic pressure decreased by 1.0 mmHg over the 12-month period. The mean pulse rate decreased by 0.5 beats/min.
3.5. Efficacy 3.5.1. Menopausal symptoms There was a significant reduction in the mean number of hot flushes with 80% of patients reporting complete relief from hot flushes after 2 months of treatment. The mean number of hot flushes per day reduced from 4.0 to 0.4 during this time and remained stable for the remainder of the study. At baseline, 179 patients were reported as symptomatic with a mean number of hot flushes of 5.0 per day. In this subgroup, the mean number of hot flushes per day was reduced by 91% from baseline to 0.4 after 2 months and the reduction remained stable for the rest of the 1 year study. Symptomatic patients with surgical menopause appeared to have more hot flushes per day
at baseline (5.9) than the naturally menopausal patients (4.7). This difference was largely due to one highly symptomatic patient who reported 30 symptoms per day at baseline. At the endpoint of the study however, the mean number of hot flushes per day in the surgical menopause subgroup had fallen to 0.2. Only 13% of patients still presented with some symptoms after 11 months of treatment, but none had hot flushes of severe intensity prohibiting continuation of current activity (compared with 20% at baseline) and only 1% had hot flushes of moderate intensity (compared with 40% at baseline). Thus after 11 months of treatment, 99% of patients were experiencing either no hot flushes or only mild ones (sensation of hotness without sweating). There was a similar pattern of reduction in the frequency of night sweats as for hot flushes. A reduction in the number of patients presenting with other symptoms was seen over the study period (Fig. 2). The incidence of vaginal dryness decreased by 76%. Libido disorders and sleep or mood disturbances reduced in : 50% of cases, osteoarticular pain and asthenia in : 30% of cases, and urinary incontinence in 22% of cases. Improvements were also noted in gynaecological examinations of vulval atrophy, presence of mucus and atrophy of vaginal smears. The effect on vaginal smears was particularly striking with 72.2% of all included patients showing an improvement after 11 months.
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3.5.2. Changes from baseline — laboratory tests Mean estradiol levels showed a mean increase of 160.8 pmol/l. These changes were similar for both types of menopause and for both regimens. Total cholesterol was statistically significantly reduced by 3.9% and LDL cholesterol by 5.1% during the study, and as expected with transdermal HRT, there was no increase in triglycerides levels. Mean plasma Calcium value was statistically significantly decreased by 1.3% and alkaline phosphatase by 22.0%. 3.6. Adhesion Adhesion of OESCLIM® was very good during the study: only 4.4% of patches applied became detached during the study. The main causes of detachment, in descending order of frequency were: rubbing (1.3%); dressing (0.7%); bath (0.7%); shower (0.7%); excess sweating (0.4%) and other causes (0.5%). No patient withdrew prematurely from the study due to patch detachment.
3.7. Patient acceptability OESCLIM® was found to be very well accepted by the patients and investigators alike with 79% of patients wishing to continue with therapy at the end of this 1 year study. Patients’ overall attitudes to treatment are shown in Table 4. Investigators assessed the treatment as effective in 96.8% of cases; well tolerated locally in 93.1% of cases and well tolerated generally in 89.5% of cases. Efficacy and tolerability were judged similar for both regimens studied. Table 4 Patient attitudes to treatment Attitudes to treatment
Percentage of patients, N= 224
Improvement in feeling of well being Effective or very effective General tolerability (well–very well) Satisfied or very satisfied with treatment Wished to continue treatment
90.7% 95.9% 88.6% 86.8% 79.0%
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4. Discussion Our study confirmed that OESCLIM® is well tolerated locally and systemically in long-term therapy. Only 4.3% of total applications (17 702) were reported as causing a local site reaction, and none of the cases required corrective treatment. This is consistent with the modest incidence of application site reactions seen with OESCLIM® in other studies. Rozenbaum reported that the incidence of application site reactions due to OESCLIM® was significantly less than those caused by Estraderm TTS® 50 (4.2% compared to 9.5%; PB 0.001) [5]. The very good local tolerability of OESCLIM® was confirmed in the fact that almost two thirds of patients reported no local skin reaction. Even for the patients who did experience a reaction, this occurred with B10% of the patches used and only 2.7% of patients actually withdrew from the study for this reason. This compares very favourably when considering patient withdrawal rates with other transdermal systems. In a 6-month trial of the matrix patch Systen® and Estraderm TTS®, 8% of patients withdrew from each group due to dermatological complaints [6]. Global tolerability of OESCLIM® was also good in the study with only 7.5% of patients withdrawing from the study because of signs of hyperestrogenism. The most frequent signs of hyperestrogenism leading to withdrawal were excessive bleeding (2.6% of patients) and mastodynia or mastosis (2.2% of patients) but these percentages were small. Patients who have experienced hyperestrogenism had it mainly during the first 3 months. This could be partially explained by the fact that patients whose menopause began several years ago may present with signs of hyperestrogenism when starting HRT. In practice, patients who experience signs of hyperestrogenism can be changed to a lower dose of estrogen. OESCLIM® is available in a wide range of doses. This means that physicians should be able to titrate doses up or down and find a regimen to suit individual patients. Good tolerability with treatment is likely to affect patient compliance. Hahn found that a major reason women stop taking HRT was the
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occurrence of withdrawal bleeding and hormonal side effects [7]. Cano also found that women who used transdermal estrogen were more compliant than those using other forms [8]. He reported that a higher percentage of women using transdermal patches rather than oral estrogen, continued HRT therapy for more than 1 year (79 vs. 54%). Our study seems to confirm that transdermal administration with low side effects can lead to good long-term compliance. After 1 year of therapy 79% of patients wished to continue with treatment, with 86.8% of patients reporting that they were satisfied or very satisfied with the therapy. These good continuation rates are encouraging and in contrast to other studies or surveys which report low continuation rates [9]. In one British survey, 51% of users stopped HRT within a year of starting [10]. The results from this study support those from previous placebo and reference controlled studies which demonstrate the efficacy of OESCLIM® in effectively reducing vasomotor symptoms such as hot flushes and night sweats [11,12]. In this 1 year study, the mean number of vasomotor symptoms per day reduced significantly on OESCLIM® from 4.0 at baseline to 0.4 after 2 months of treatment and until the end of the study. OESCLIM® was also effective in reducing other menopausal symptoms such as vaginal dryness (76% reduction) and mood disturbances (50% reduction). The treatment of vasomotor symptoms is one of the primary reasons women seek treatment at the menopause, and efficacy of treatment is needed if women are to continue therapy. However, HRT also needs to be well-tolerated if patients are to continue therapy in the long term. Patients are known to continue therapy if they perceive a benefit from therapy, such as a reduction in symptoms, and to discontinue therapy because of side effects, bleeding and anxieties over breast cancer [13]. OESCLIM® was also shown to be a reliable patch with few detachments (4.4%) during normal use. Other studies have reported the good adherence properties of OESCLIM® [11]. In a comparative study with Estraderm TTS®, only 6% of OESCLIM® became detached compared to 11% of Estraderm TTS® patches.
In conclusion, OESCLIM® is a very good first line therapy for the treatment of menopausal symptoms. It offers effective treatment with good tolerability over the long term which may improve patient compliance. OESCLIM® is indicated for low-dose initiation of therapy and has demonstrated excellent efficacy at this dose [12]. In addition, the variety of doses available give physicians the ability to titrate doses to maximise patient acceptability.
Acknowledgements The authors wish to thank their colleagues, listed below, who participated in the clinical study reported in this publication:l France Dr C. Scheffler, Essey-Les-Nancy; Dr J.-P. Blanchere, Caen; Dr B. Juan Bringuy, Corbeil Essonnes; Dr P. Penciolelli, La Ferte Alais; Dr S. Dat, Toulouse; Dr D. Wiel-Masson, Chartres; Dr B. Rossinot-Meot, Nancy; Dr D. Elia, Paris; Dr G. Blazquez, Corbeil Essonnes; Dr A. Percie du Sert, Longjumeau; Dr K. Do Trinh, Chilly Mazarin; Dr M.-A. De Crecy, Ste Genevieve des Bois; Dr J. Mercier, Paris; Dr C. Coussirat-Coustere, Villejuif; Dr F. Lorgere, Ste Genevieve des Bois; Dr O. Demeure-Melcion, Arpajon; Dr B. Ferron Leymarie, Champigny sur Marne; Dr N. Guerre-Lebhar, Ste Genevieve des Bois; Dr C. Norbert, La Ferte Alais. Belgium Dr S. Rozenberg, Bruxelles; Dr E. Markowicz, Bruxelles; Dr J. Schwers, Bruxelles; Dr J. Vandromme, Bruxelles; Dr E. Van Roosendaal, Bruxelles. Switzerland Dr C. Ko¨nig, Bern; Dr C. Reber, Niederbipp; Dr G. Boss, Bern; Dr A. Haenel, Solothurn. Germany Dr H. Lubbert, Berlin; Dr M. Nehmzow, Griefswald; Dr S. Gurr, Berlin; Dr C. Albus, Greifswald.
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United Kingdom Dr M. Pugh, London; Dr J. Montgomery, Brighton. The study was supported by Laboratoires FOURNIER, Dijon, France. The authors wish to thank the members of the FOURNIER study team: Dr M. Guy; Dr H. Chadha-Boreham; Dr G. Tachon.
References [1] Hammond CB. Estrogen replacement therapy: What the future holds. Am J Obstet Gynecol 1989;161:1864–8. [2] Munoz A. OESCLIM®: an advanced delivery system for HRT. Maturitas: 1999;33 (Suppl. 1):S39–S47. [3] Guichard JP, Sauron R, Jones A. Comparison of the pharmacokinetics of 17b-estradiol after a single 4-day application of OESCLIM® 50, OESCLIM® 100 and VIVELLE® 0.05 (MENOREST® 50) transdermal delivery systems, J Clin Pharmacol 1999; 39:811–816. [4] Guichard JP, Sauron R, Dutertre JP, et al. A pilot study of the comparative bioavailability of estradiol from two different estradiol transdermal systems; Oesclim® 50 and Systen® 50. Curr Ther Res 1995;56:1022–32. [5] Rozenbaum H, Birkhau¨ser M, De Nooyer C, et al. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) II. Local skin tolerability. Maturitas 1996;25:175–85.
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[6] Van Leusden H, Albertyn G, Verlaine C, Van Ruymbeke J. A comparative multicentre study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. Int J Fertil 1993;38(4):210– 8. [7] Hahn R. Compliance considerations with estrogen replacement: Withdrawal bleeding and other factors. Am J Obstet Gynecol 1989;161:1854. [8] Cano A. Compliance to hormone replacement therapy in menopausal women controlled in a third level academic centre. Maturitas 1995;20:91 – 9. [9] Schneider HPG. Cross national study of women’s use of hormone replacement therapy in Europe. Int J Fertil 1997;42:365 – 75. [10] Hope S, Rees MCP, Radcliffe J. Why do British women start and stop hormone replacement therapy? J Br Menopause Soc 1995;12:16 – 7. [11] Rozenbaum H, Birkhau¨ser M, De Nooyer C, et al. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) I. Tolerability, adhesion and efficacy. Maturitas 1996;25:161 – 73. [12] Utian WH, Burry KA, Archer DF, Gallagher JC, The Esclim® Study Group et al. Efficacy and safety of low, standard and high dosages of an estradiol transdermal system (Esclim®) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients, Am J Obstet Gynecol 1999;181(1):71– 79. [13] Rayanne S, Berman RS, Epstein RS, Lydick E. Risk factors associated with women’s compliance with estrogen replacement therapy. J Women’s Health 1997;6:219 – 26.
The long-term tolerability and efficacy of OESCLIM®: results of a 1-year study R. Taurelle a,*, M. L’Hermite b, W. Haenggi c, C. Lauritzen d, J.W. Studd e a
Ser6ice Gynicologie, Hoˆpital Bouciaut, 78 Rue de la Con6ention, 75730 Paris Cedex 15, France b Hoˆpital Brugmann, Brussels, Belgium c Uni6ersitats-Frauenklinik und Kantonales Frauenspital, Bern, Switzerland d Ulm, Germany e Lister Hospital, London, UK
Abstract Objecti6es: A 1-year, open-label, non-comparative study evaluated the long-term tolerability and acceptability of a new generation matrix patch in post menopausal women with estrogen deficiency. Methods: Menopausal women (224) from 37 centres in five European countries received OESCLIM® 50 mg/d (17-b estradiol) for 3 months, titrated if necessary to either 25 or 100 mg/d for a further 9 months. Patients received either a continuous or discontinuous estradiol regimen with concomitant sequential progestogen (except hysterectomised patients). Skin tolerability was assessed by patient diaries and questionnaires. Global tolerability, efficacy, laboratory parameters and global acceptability were also monitored. Results: Almost two-thirds of women did not experience any kind of skin reaction and only 4.3% of all applications (752/17 702) caused site reactions. Of these, the majority caused only slight or no discomfort (63.2%). Only 0.37% of total applications required patch removal; none required therapy. A low percentage of patients withdrew due to tolerability issues: 2.7% due to skin reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after 2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no increase in triglyceride levels. Investigators assessed treatment as effective in 96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in 89.5%. At the end of this 1 year study, 79% of patients wished to continue therapy. Conclusion: OESCLIM® is well tolerated locally and systemically in long-term therapy with a high proportion of patients wishing to continue therapy after 1 year. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Transdermal; Estradiol; OESCLIM®; HRT; Tolerability; Compliance
1. Introduction and aims The menopause is a period of great physiological change in a woman’s life. The ovaries begin to
* Corresponding author.
fail in their production of sex hormones and estrogen levels gradually decrease over a number of years. Estrogen deficiency may result in symptoms which can be at best a nuisance, and at worse, debilitating and it is estimated that 85% of women will suffer from some kind of vasomotor symptom during this time [1].
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Hormone replacement therapy (HRT) and in particular, estrogen therapy was developed as long ago as the 1940s to relieve these symptoms. Since then, there have been many innovations and advances which have allowed HRT to become one of the most effective prophylactic treatments that physicians can prescribe for their patients. Despite the many benefits associated with HRT, compliance with HRT is still low. One of the reasons women discontinue therapy is possible side effects resulting from poor tolerability of existing HRT products. OESCLIM® (or ESCLIM® or ESCLIMA®) is an innovative new transdermal HRT product delivering 17-b estradiol for the relief of menopausal symptoms. Its non-acrylic foam backing makes it unique among transdermal patches as it is extensible and flexible, making it more comfortable for patients to wear. Pharmacokinetic studies have shown OESCLIM® to provide an improved pharmacokinetic profile compared to other transdermal systems including Estraderm TTS® 50 [2], Menorest®/Vivelle® [3] and Systen® [4]. It has also been shown to have improved adhesivity and local tolerability in a comparative study with Estraderm TTS® 50 [5]. The aim of this study was to evaluate the long-term tolerability of OESCLIM® in treating post menopausal women with estrogen deficiency and to assess patients’ response to long-term therapy.
2. Methods The study was a well-designed, open-label, noncomparative clinical study conducted in 37 centres in five European countries (UK, France, Germany, Belgium, Switzerland). The study received ethics committee approval according to the legislation of each country, and was conducted to Good Clinical Practice standards.
2.1. Patient selection Caucasian women attending the study clinics were selected for the study if they fulfilled a number of selection criteria (see Table 1). Patients
who had previously received treatments other than transdermal estrogen were eligible after a one month wash-out period. If women had undergone an oophorectomy, they were also eligible for inclusion 1 month after the operation. After a screening visit to assess eligibility, patients who gave informed consent to participate returned to the clinic to begin therapy (day 0). A further three visits were required between days 8 and 15 of months 3, 7 and 12. A final interview was conducted during the first week of month 13.
2.2. Treatment groups All patients were treated, for the first 3 months of study, with OESCLIM® 50 delivering 50 mg/d of 17-b estradiol. If required after this time, the dose was titrated to either 25mg/d or 100mg/d, according to response and tolerability. Patients were given either a continuous or a discontinuous estradiol regimen at the discretion of the investigator. Discontinuous regimens comprised 24–28 days of estrogen treatment followed by a treatment-free period of between 2 and 7 days. OESCLIM® was applied to the buttocks twice weekly (one for 3 days; then a second patch for 4 days). Alternate buttocks were used to vary the application site. In line with prescribing information, the skin was to be clean, dry, healthy and not treated with creams or lotions before application. Patients who had not undergone a hysterectomy, were also prescribed an oral, concomitant progestogen to prevent endometrial hyperplasia. This was administered sequentially for 12–16 days at the end of the estrogen therapy. DyTable 1 Patient selection criteria Post menopausal women suffering symptoms of estrogen deficiency through either a natural or surgical menopause Estradiol and FSH plasma levels within postmenopausal range No history of chronic skin disease or cutaneous contact allergy No contraindication for estrogen therapy Not on concomitant treatments likely to influence the results of the study
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drogesterone was the only non-androgenic progestogen available in all European countries involved in the study, but other progestogens could be chosen from an approved list.
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asthenia and mood. At the screening and final clinical visits, vaginal smears were taken for the assessment of vaginal trophicity. The investigator also clinically assessed vulval trophicity and cervical mucus.
2.3. Measurements 2.3.1. Tolerability 2.3.1.1. Patient diaries. Patients were asked to record details of any skin reactions. These included the date of patch application and removal; site and duration of reaction; type of reaction; degree of discomfort and whether the reaction required the patch to be removed. The degree of discomfort and type of each reaction were assessed using pre-defined headings (no discomfort, slight discomfort, discomfort, considerable discomfort and redness, spots, swelling, itching, or burning sensation). Patients were also assessed at clinic visits and details of any corrective treatments noted. Isolated erythema which lasted B 1 h after removal of the patch were not included. General tolerability was assessed in addition to local skin tolerability. Patients were asked to record signs of hyperestrogenism (menorrhagia, mastodynia, nausea, abdominal pain and bloating, heavy legs, and oedema). Any adverse events including withdrawal bleeding or vaginal bleeding were also noted, along with information on the abundance and duration of bleeds. During clinical examinations, data were collected on a number of physiological parameters including blood pressure, heart rate, body weight and laboratory tests were conducted to assess changes in estradiol levels and lipid profiles. Blood samples were taken outside of sequence of concomitant progestogen. 2.3.2. Efficacy assessments The study was not designed to demonstrate the efficacy of OESCLIM®; however, efficacy parameters were assessed by recording the number of vasomotor symptoms (hot flushes and night sweats) experienced at baseline and at each visit. Hot flushes were graded according to severity. Seven other symptoms were recorded including urinary incontinence, vaginal dryness, libido disorders, osteoarticular pain, quality of sleep,
2.3.3. Patient satisfaction At the end of the study period, the investigator qualitatively assessed general and local tolerability for each patient. Patients were asked to assess their general condition and feeling of well-being, general tolerability and satisfaction with treatment. They were also asked whether they would like to continue treatment or not. 2.4. Statistical analysis Statistical analyses used mainly descriptive and qualitative methods. Inferential methods were used only for variables relating to local tolerability and biological parameters. For local tolerability, 95% confidence intervals were calculated and for biological values, changes from baseline to endpoint were analysed at the 10% significance level.
3. Results
3.1. Patient characteristics Of 305 patients selected, 224 were eligible for inclusion in the study, with an age range from 39 to 72 years. As expected, there was an age range difference between the women who had undergone a natural menopause, and those who had undergone a surgical menopause, where there was a higher proportion of patients under the age of 45 years. The baseline characteristics of the patients included in the study are recorded in Table 2. Of the natural menopause patients, 70 patients (40%) received a continuous regimen, and 107 (60%) received a discontinuous regimen. The split was more uneven in the women who had undergone a surgical menopause because of the high number allocated to receive a continuous regimen, 38 (81%). Only nine patients (19%) with surgical
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Table 2 Patient characteristics at baseline, by type of menopausea Characteristics
Natural menopause n = 177
Surgical menopause n =47
All patients n = 224
Age (years) Age at onset of menopause Time since menopause (years) Hot flushes per day
52.7 48.9 3.9 3.9
52.6 46.4 6.2 4.5
52.7 48.3 4.5 4.0
(95.6) (9 3.6) (9 4.9) (94.0)
(97.2) (9 7.4) ( 9 7.2) (95.6)
( 9 5.9) ( 94.8) (9 5.6) ( 94.4)
a
Mean9 SD. Data on the ‘age at onset of menopause’ and the ‘time since menopause’ was unavailable in 19 natural menopause patients.
menopause were given a discontinuous regimen. Overall, however, the split between the two groups was comparable: 108 patients (48%) received a continuous regimen and 116 (52%) received discontinuous therapy.
3.1.1. Vasomotor symptoms At baseline, 85.5% of patients were found to be suffering from vasomotor symptoms, with a mean number of four hot flushes per day. The number of hot flushes experienced by patients per day ranged from 0 to 30, with patients in the surgical menopause group having a higher mean number of flushes per day than those who had undergone a natural menopause. In relation to night sweats, there were no important differences between the two groups. However, 27.2% of patients experienced very frequent night sweats; 27.2% frequently; 15.2% had them rarely, and 30.4% of patients had no night sweats at all. 3.2. Patient participation and withdrawal One hundred and seventy-five patients completed the study (78%) according to the study protocol. Forty-nine patients withdrew or were withdrawn from the study during the 12-month period. Of these, only 34 (15.1%) withdrew due to adverse events. Other reasons for withdrawal included: five patients who withdrew consent; two patients were lost to follow-up; six were ineligible after re-assessment; two withdrew for other reasons. The main adverse events leading to withdrawal were signs of hyperestrogenism (17 patients) and application site reactions (six patients).
3.2.1. Dose titration All patients were placed on the 50 mg/d dose for the first 3 months of the study. After that time, nearly a quarter of the patients (51 patients, 22.8%) were titrated to a lower dose of 25 mg/day. This was mainly due to symptoms of hyperestrogenism, but this group were effectively maintained on the low dose for the remainder of the study. Twelve patients (5.4%) needed the dose to be titrated upwards to 100 mg/day, due to lack of efficacy. Only five patients changed dose more than once during the study, and the remaining 156 patients (69.6%) remained on the 50 mg/d dose they had started on. 3.3. Local skin tolerability Skin tolerability data was available for 222 patients who applied a total of 17 702 patches over the course of the study. Only 4.3% of all applications (752/17 702) caused site reactions, almost two-thirds of the women did not experience any kind of skin reaction, and for the majority of those who did have a reaction, this occurred with only 1–10% of the patches they used, as shown in Fig. 1 (distribution of the percentage of applications per patient which caused a site reaction). The mean number of local reactions were similar in each of the treatment regimens. The women on discontinuous therapy had 3.0 reactions per patient (mean), whereas the patients in the continuous therapy group had 3.8 reactions per patient over the year. The type of skin reaction experienced is shown in Table 3. The pattern of site reactions was of the same magnitude across each dosage and for the different regimens. The continuous regimen group
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Fig. 1. Percentage of total applications per patient which caused reactions.
had 402/9073 reactions (4.4%) and there were 350/8629 reactions (4.1%) in the discontinuous group. Redness and itching often occurred together and were the most common types of reaction noted. The majority of reactions (68%) occurred during the first 6 months of treatment. The median duration of reaction was only 12 h. Of the reactions experienced, the majority caused only slight or no discomfort (63.2%) and only 8.8% of total reactions required the patch to be removed. This represented only 0.37% of the total applications over the entire study period and none of these required any corrective therapy. The six patients who withdrew prematurely because of site reactions were all receiving the 50 mg/d dose, split equally between the discontinuous and continuous regimens.
3.4. Global tolerability Global tolerability with OESCLIM® was good with only 17 patients (7.5%) having to withdraw
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from the study due to signs of hyperestrogenism. A total of 138 patients (61.6%) experienced at least one adverse event attributed to HRT, with hyperestrogenism and breakthrough bleeding/ spotting being the most common symptoms. However, 36.6% of patients experienced hyperestrogenic adverse events and of these patients, during the first 3 months of HRT, 24.1% experienced adverse events coded as ‘altered hormone levels’. This decreased to 7.6% of patients during the following 3 months and then fell to B 5% for the rest of the study duration. The most frequent hyperestrogenic symptoms recorded were breast pain (68 patients; 30.4%), weight gain (14 patients; 6.3%) and menorrhagia (12 patients; 5.4%). Apart from adverse events related to bleeding, there were not clinically important differences between the natural and surgical menopause groups. The total study group included 141 patients who had not undergone a complete hysterectomy, and almost 97% had at least one episode of withdrawal bleeding over the year. However, this was an expected event as progestogen was given sequentially for these patients. The average duration of bleeding was 4.3 days per month, but higher doses and a continuous regimen led to more abundant bleeds. Breakthrough bleeding was only induced in 14.1% of the monthly cycles assessed, and the majority of these (67.9%) were due to spotting. Other adverse events included symptoms related to urogenital system (34 patients; 15.2%); ‘body as a whole’ (30 patients; 13.4%) and ‘metabolic’ or nutritional disorders (19 patients; 8.5%). These did not appear to be related to dose or menopause-type.
Table 3 Types of application site reaction at each dosea Type of reaction
25 mg/d, r = 134b
50 mg/d, r = 607b
Redness Itching Spots Burning sensation Swelling
69 104 24 30 6
484 354 141 100 53
a b
100 mg/d, r = 11b 4 10 1 0 1
Total for all dosages, r =752b 557 468 166 130 60
(3.1%) (2.6%) (0.9%) (0.7%) (0.3%)
Number (% of total applications). Data on type of reaction missing in four cases. r= number of reactions. Reactions could be categorised as more than one type.
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Fig. 2. Percentage of patients reporting other symptoms at baseline (Vi) and after 11 months treatment (V3).
There was a slight trend towards weight gain in the study, but this was low ( + 0.8 kg) and there was a wide range of weight change. Most of the mean weight gain appeared very early in the study (by the end of month 3) and mean weight stabilised thereafter with only minor fluctuations. Monitoring of other vital signs revealed that there were slight decreases in both mean blood pressure and pulse from baseline to end point. Systolic pressure decreased by 0.9 mmHg, and diastolic pressure decreased by 1.0 mmHg over the 12-month period. The mean pulse rate decreased by 0.5 beats/min.
3.5. Efficacy 3.5.1. Menopausal symptoms There was a significant reduction in the mean number of hot flushes with 80% of patients reporting complete relief from hot flushes after 2 months of treatment. The mean number of hot flushes per day reduced from 4.0 to 0.4 during this time and remained stable for the remainder of the study. At baseline, 179 patients were reported as symptomatic with a mean number of hot flushes of 5.0 per day. In this subgroup, the mean number of hot flushes per day was reduced by 91% from baseline to 0.4 after 2 months and the reduction remained stable for the rest of the 1 year study. Symptomatic patients with surgical menopause appeared to have more hot flushes per day
at baseline (5.9) than the naturally menopausal patients (4.7). This difference was largely due to one highly symptomatic patient who reported 30 symptoms per day at baseline. At the endpoint of the study however, the mean number of hot flushes per day in the surgical menopause subgroup had fallen to 0.2. Only 13% of patients still presented with some symptoms after 11 months of treatment, but none had hot flushes of severe intensity prohibiting continuation of current activity (compared with 20% at baseline) and only 1% had hot flushes of moderate intensity (compared with 40% at baseline). Thus after 11 months of treatment, 99% of patients were experiencing either no hot flushes or only mild ones (sensation of hotness without sweating). There was a similar pattern of reduction in the frequency of night sweats as for hot flushes. A reduction in the number of patients presenting with other symptoms was seen over the study period (Fig. 2). The incidence of vaginal dryness decreased by 76%. Libido disorders and sleep or mood disturbances reduced in : 50% of cases, osteoarticular pain and asthenia in : 30% of cases, and urinary incontinence in 22% of cases. Improvements were also noted in gynaecological examinations of vulval atrophy, presence of mucus and atrophy of vaginal smears. The effect on vaginal smears was particularly striking with 72.2% of all included patients showing an improvement after 11 months.
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3.5.2. Changes from baseline — laboratory tests Mean estradiol levels showed a mean increase of 160.8 pmol/l. These changes were similar for both types of menopause and for both regimens. Total cholesterol was statistically significantly reduced by 3.9% and LDL cholesterol by 5.1% during the study, and as expected with transdermal HRT, there was no increase in triglycerides levels. Mean plasma Calcium value was statistically significantly decreased by 1.3% and alkaline phosphatase by 22.0%. 3.6. Adhesion Adhesion of OESCLIM® was very good during the study: only 4.4% of patches applied became detached during the study. The main causes of detachment, in descending order of frequency were: rubbing (1.3%); dressing (0.7%); bath (0.7%); shower (0.7%); excess sweating (0.4%) and other causes (0.5%). No patient withdrew prematurely from the study due to patch detachment.
3.7. Patient acceptability OESCLIM® was found to be very well accepted by the patients and investigators alike with 79% of patients wishing to continue with therapy at the end of this 1 year study. Patients’ overall attitudes to treatment are shown in Table 4. Investigators assessed the treatment as effective in 96.8% of cases; well tolerated locally in 93.1% of cases and well tolerated generally in 89.5% of cases. Efficacy and tolerability were judged similar for both regimens studied. Table 4 Patient attitudes to treatment Attitudes to treatment
Percentage of patients, N= 224
Improvement in feeling of well being Effective or very effective General tolerability (well–very well) Satisfied or very satisfied with treatment Wished to continue treatment
90.7% 95.9% 88.6% 86.8% 79.0%
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4. Discussion Our study confirmed that OESCLIM® is well tolerated locally and systemically in long-term therapy. Only 4.3% of total applications (17 702) were reported as causing a local site reaction, and none of the cases required corrective treatment. This is consistent with the modest incidence of application site reactions seen with OESCLIM® in other studies. Rozenbaum reported that the incidence of application site reactions due to OESCLIM® was significantly less than those caused by Estraderm TTS® 50 (4.2% compared to 9.5%; PB 0.001) [5]. The very good local tolerability of OESCLIM® was confirmed in the fact that almost two thirds of patients reported no local skin reaction. Even for the patients who did experience a reaction, this occurred with B10% of the patches used and only 2.7% of patients actually withdrew from the study for this reason. This compares very favourably when considering patient withdrawal rates with other transdermal systems. In a 6-month trial of the matrix patch Systen® and Estraderm TTS®, 8% of patients withdrew from each group due to dermatological complaints [6]. Global tolerability of OESCLIM® was also good in the study with only 7.5% of patients withdrawing from the study because of signs of hyperestrogenism. The most frequent signs of hyperestrogenism leading to withdrawal were excessive bleeding (2.6% of patients) and mastodynia or mastosis (2.2% of patients) but these percentages were small. Patients who have experienced hyperestrogenism had it mainly during the first 3 months. This could be partially explained by the fact that patients whose menopause began several years ago may present with signs of hyperestrogenism when starting HRT. In practice, patients who experience signs of hyperestrogenism can be changed to a lower dose of estrogen. OESCLIM® is available in a wide range of doses. This means that physicians should be able to titrate doses up or down and find a regimen to suit individual patients. Good tolerability with treatment is likely to affect patient compliance. Hahn found that a major reason women stop taking HRT was the
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occurrence of withdrawal bleeding and hormonal side effects [7]. Cano also found that women who used transdermal estrogen were more compliant than those using other forms [8]. He reported that a higher percentage of women using transdermal patches rather than oral estrogen, continued HRT therapy for more than 1 year (79 vs. 54%). Our study seems to confirm that transdermal administration with low side effects can lead to good long-term compliance. After 1 year of therapy 79% of patients wished to continue with treatment, with 86.8% of patients reporting that they were satisfied or very satisfied with the therapy. These good continuation rates are encouraging and in contrast to other studies or surveys which report low continuation rates [9]. In one British survey, 51% of users stopped HRT within a year of starting [10]. The results from this study support those from previous placebo and reference controlled studies which demonstrate the efficacy of OESCLIM® in effectively reducing vasomotor symptoms such as hot flushes and night sweats [11,12]. In this 1 year study, the mean number of vasomotor symptoms per day reduced significantly on OESCLIM® from 4.0 at baseline to 0.4 after 2 months of treatment and until the end of the study. OESCLIM® was also effective in reducing other menopausal symptoms such as vaginal dryness (76% reduction) and mood disturbances (50% reduction). The treatment of vasomotor symptoms is one of the primary reasons women seek treatment at the menopause, and efficacy of treatment is needed if women are to continue therapy. However, HRT also needs to be well-tolerated if patients are to continue therapy in the long term. Patients are known to continue therapy if they perceive a benefit from therapy, such as a reduction in symptoms, and to discontinue therapy because of side effects, bleeding and anxieties over breast cancer [13]. OESCLIM® was also shown to be a reliable patch with few detachments (4.4%) during normal use. Other studies have reported the good adherence properties of OESCLIM® [11]. In a comparative study with Estraderm TTS®, only 6% of OESCLIM® became detached compared to 11% of Estraderm TTS® patches.
In conclusion, OESCLIM® is a very good first line therapy for the treatment of menopausal symptoms. It offers effective treatment with good tolerability over the long term which may improve patient compliance. OESCLIM® is indicated for low-dose initiation of therapy and has demonstrated excellent efficacy at this dose [12]. In addition, the variety of doses available give physicians the ability to titrate doses to maximise patient acceptability.
Acknowledgements The authors wish to thank their colleagues, listed below, who participated in the clinical study reported in this publication:l France Dr C. Scheffler, Essey-Les-Nancy; Dr J.-P. Blanchere, Caen; Dr B. Juan Bringuy, Corbeil Essonnes; Dr P. Penciolelli, La Ferte Alais; Dr S. Dat, Toulouse; Dr D. Wiel-Masson, Chartres; Dr B. Rossinot-Meot, Nancy; Dr D. Elia, Paris; Dr G. Blazquez, Corbeil Essonnes; Dr A. Percie du Sert, Longjumeau; Dr K. Do Trinh, Chilly Mazarin; Dr M.-A. De Crecy, Ste Genevieve des Bois; Dr J. Mercier, Paris; Dr C. Coussirat-Coustere, Villejuif; Dr F. Lorgere, Ste Genevieve des Bois; Dr O. Demeure-Melcion, Arpajon; Dr B. Ferron Leymarie, Champigny sur Marne; Dr N. Guerre-Lebhar, Ste Genevieve des Bois; Dr C. Norbert, La Ferte Alais. Belgium Dr S. Rozenberg, Bruxelles; Dr E. Markowicz, Bruxelles; Dr J. Schwers, Bruxelles; Dr J. Vandromme, Bruxelles; Dr E. Van Roosendaal, Bruxelles. Switzerland Dr C. Ko¨nig, Bern; Dr C. Reber, Niederbipp; Dr G. Boss, Bern; Dr A. Haenel, Solothurn. Germany Dr H. Lubbert, Berlin; Dr M. Nehmzow, Griefswald; Dr S. Gurr, Berlin; Dr C. Albus, Greifswald.
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United Kingdom Dr M. Pugh, London; Dr J. Montgomery, Brighton. The study was supported by Laboratoires FOURNIER, Dijon, France. The authors wish to thank the members of the FOURNIER study team: Dr M. Guy; Dr H. Chadha-Boreham; Dr G. Tachon.
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