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OESCLIM®: an advanced delivery system for HRT
Maturitas 33 (1999) S39 – S47 www.elsevier.com/locate/maturitas
OESCLIM®: an advanced delivery system for HRT Alain Munoz * Laboratoires Fournier, 50 Rue de Dijon, 21121 Daix, France
Abstract Aims: Transdermal estradiol offers a number of advantages over traditional oral routes of hormone replacement therapy (HRT) because it is not subject to the hepatic first-pass effect. However, transdermal systems need to balance adhesion, tolerability, and flux if they are to be effective. OESCLIM® is a transdermal 17-b estradiol HRT system designed to address the problems of conventional transdermal patches and offer optimal adhesion and tolerability in an effective HRT system. This paper reviews some of the data on OESCLIM® with reference to its delivery system. Results: The innovative technology used in OESCLIM® results in a smooth pharmacokinetic profile throughout the 3–4 day application period. In recent pharmacokinetic studies, OESCLIM® 50 provided a more consistent release of hormone than Estraderm TTS® 50 and higher mean estradiol levels than Systen® and Vivelle®. This smooth pharmacokinetic profile is also maintained whether OESCLIM® is attached to different body sites. The local skin tolerability of OESCLIM® is good. One study reported that OESCLIM® 50 caused less than half the number of skin reactions as Estraderm TTS® 50 (4.2% compared to 9.5%). OESCLIM® has also been shown to have fewer detachments than Estraderm TTS® (6% compared to 11%). Both differences were statistically significant (PB 0.001). A study has shown OESCLIM® to be as effective as Estraderm TTS® at reducing vasomotor symptoms even in highly symptomatic women. Conclusion: OESCLIM® is a very good first-line choice for estrogen replacement therapy (ERT) or HRT providing effective therapy with optimum adhesion, flux and tolerability profiles. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: HRT; OESCLIM®; Tolerability; Transdermal
1. Introduction The identification of an optimal delivery system for hormone replacement therapy (HRT) has been a concern for the medical profession since the introduction of the first estrogen replacement therapy over 50 years ago. During that time, a variety of systems have emerged with varying degrees of acceptability to patients and doctors. * Tel.: +33-380-447500; fax: + 33-380-447510.
These include oral preparations, transdermals, gels, injections, and subcutaneous implants. Transdermal administration offers a number of advantages over other more traditional oral routes. Orally-delivered estradiol (E2) is extensively metabolized in the gastro-intestinal tract to form a less active compound, estrone (E1). Estradiol delivered orally is subject to first-pass metabolism in the liver which reduces the estradiol levels available. The low bioavailability of oral estrogens means that oral routes of delivery
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require high initial doses to achieve therapeutic plasma levels. In addition, estrogens delivered orally can alter the synthesis of certain liver proteins [1]. Since the transdermal route avoids biological degradation because of the hepatic firstpass effect, it is possible to substantially reduce the dosage delivered compared to orals. A 40 – 80 fold lower dose of estradiol delivered transdermally can be used to achieve the same efficacy as orally-delivered estrogen. In addition, the transdermal route is more appropriate for certain types of patients than oral routes because they have less impact on hepatic metabolism and other risk factors such as high levels of triglycerides (e.g. diabetics, smokers, hypertriglyceridaemic patients). In order for a transdermal system to be effective, it must facilitate long term patient compliance by balancing three factors: adhesion, tolerability, and flux. (Fig. 1). An imbalance in any one of these factors may cause the system to fail overall. For example, if the flux of the drug is not sufficient, then the tolerability may be very good, but at the expense of efficacy. Similarly, if the adhesion is poor, then the system will again fail because it will become detached, disrupting the delivery of estrogen to the woman. Transdermal systems need to reach optimum levels of all three factors in order for the system to be acceptable to patients and their doctors. If this is achieved then transdermal systems offer the best first-line treatment for women seeking relief of vasomotor symptoms around the time of the menopause.
Fig. 1. Balance of factors needed for transdermal HRT delivery systems.
2. OESCLIM® OESCLIM® (ESCLIM®/ESCLIMA®) is a new transdermal 17-b estradiol preparation recently developed by Groupe Fournier. It was developed to address some of the problems associated with existing patches such as poor adhesion and local skin irritation. The patented matrix system used, is a significant advance in transdermal technology. It is foam backed, giving added comfort, and has a unique profile in the myriad of available HRT products [2,3]. It also differentiates OESCLIM® from other transdermal preparations available by offering optimum adhesion and tolerability profiles. OESCLIM® also offers effective therapy at lower doses than oral estrogen products, and its stable pharmacokinetic profile eliminates the peaks and troughs in plasma concentrations associated with oral routes [4]. These advances over oral and conventional transdermal products offer physicians the possibility of delivering real patient benefits.
3. Existing transdermal technology Conventional transdermal estrogen therapy was first introduced in 1985 and is still available today. First generation transdermal systems carried the hormones within a reservoir containing an alcoholic gel. The use of this carrier system was often associated with a local skin irritation at the site of application, such as redness and swelling. Early trials reported local side effects in 17–58% of patients. This relatively high proportion of reactions led to poor compliance amongst patients and resulted in approximately 8% of patients discontinuing therapy [3]. In these preparations, the drug is gradually discharged from the reservoir over the application period (Fig. 2). These systems are relatively rigid because of the need to contain the drug within the reservoir, and can have problems with adhesion, skin tolerability and comfort. And this imbalance between adhesion, tolerability and flux led to problems with patient acceptability.
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ogy (Fig. 3). Its patented system delivers a natural human estrogen, 17-b estradiol, through a unique non-acrylic, beige-colored, self-adhesive matrix composition which provides very good patient comfort [Fig. 4]. The OESCLIM® matrix patch is composed of two layers: 1. the matrix system, and 2. a peelable bottom layer of siliconized polyester film which protects the face of the matrix until it is removed before application of OESCLIM® to the skin. The matrix system itself also consists of two layers. The layer attached to the skin is the ethylene vinyl acetate (EVA) matrix. This matrix
Fig. 2. Traditional transdermal reservoir system. Fig. 3. New generation matrix system.
A significant advance over conventional reservoir systems came with the development of matrix systems. In this type of system, the active ingredient is included in a polymer matrix. This is bound to a backing film which forms the exterior surface of the patch. The majority of transdermal systems currently available are acrylic matrix systems, and although their pharmacokinetic profile is more stable than reservoir systems, there are still problems with adhesion, skin tolerability, and comfort which need to be overcome if optimum performance is to be a reality. 4. Advanced transdermal technology of OESCLIM® OESCLIM® is the only transdermal HRT product to use an innovative new matrix technol-
Fig. 4. OESCLIM® matrix composition.
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contains the active compound 17-b estradiol, excipients and is self-adhesive. It controls the release of estradiol to the skin, and determines the adhesive properties of the system. This layer has good drug-delivery characteristics resulting in a smooth pharmacokinetic profile [5 – 7]. The EVA matrix uses high-quality components to provide optimal skin tolerability and does not use skin penetration enhancers which can be potentially irritative agents. The adhesives used have high cohesive properties to ensure optimal adhesion and easy removal of the system at the end of the application period, without leaving adhesive residues on the skin. The top layer of the patch consists of an alveolar foam backing, which protects the EVA matrix. The elastic properties of this unique foam backing make it extensible, soft, and flexible, allowing it to move with the skin, whilst staying firmly attached. The components of the OESCLIM® system, such as the beige color and advanced flexible backing, were developed after extensive research into women’s preferences for a transdermal system. Research was conducted across Europe to enable the development of a patch which would be widely accepted. Dose adaptation is important in successfully initiating HRT and in patient compliance as it allows physicians to tailor treatment to individual women. OESCLIM® is available in some countries, in five doses, delivering 25, 37.5, 50, 75, and 100 mg/24 h of estradiol. This allows great flexibility when titrating doses.
5. Pharmacokinetics of OESCLIM® The innovative technology used in the development of OESCLIM® has resulted in a stable pharmacokinetic profile. Estradiol is released from the EVA matrix by passive diffusion at a constant rate throughout the application period (3–4 days). This is because the concentration gradient of estradiol between the matrix and the skin remains constant during the absorption process. Estradiol is thus permanently supplied to the skin from the matrix.
Physiological serum levels of estradiol are reached 4 h after application and peak serum levels after 24 h. During the application of OESCLIM®, the estradiol/estrone serum concentrations ratio is close to 1, the physiological premenopausal value. There is no accumulation of estradiol, even after repeated doses of OESCLIM®. Estradiol serum levels decrease on removal of the patch, and serum concentrations return to baseline 8 h after removal of the patch [8]. In recent pharmacokinetic studies, OESCLIM® 50 provided a more consistent release of hormone than Estraderm TTS® 50 [6] and higher mean estradiol levels than Systen® [5]. When OESCLIM® 50 was compared to Estraderm TTS® 50, the area under curve (AUC) values were found to be approximately equivalent. However, the estradiol serum concentrations obtained with OESCLIM® were more stable over the 3–4 day application period. Fig. 5 shows the mean estradiol serum levels of the two systems, using two clinically-available doses of OESCLIM® [6]. One of the first matrix estradiol patches to be available in the United States was Vivelle®, known in Europe as Menorest®. When compared to this product in a randomized cross-over study involving 24 patients, OESCLIM® produced higher mean estradiol levels over 4 days of treatment. The good pharmacokinetic profile of OESCLIM® was also accompanied by better adhesion characteristics [7]. During repeated applications, the intra-subject variability was very low, at 2.5%. Low intra-subject variability is particularly important when considering adjusting a patient’s dose to aid compliance and reduce side effects, or when initiating treatment. The low variability between patients is amongst the lowest in commercially-available agents, in particular in comparison with oral products such as ethinyl estradiol. The new technology of OESCLIM® which is able to offer a predictable ratio of dose to serum estrogen concentration, means that physicians can be confident in adjusting treatment to suit individual patients.
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Fig. 5. Mean estradiol serum levels for 3-day application (24 women).
When using a transdermal patch, the site of application needs to be changed regularly to optimize local skin tolerance. Studies conducted on the pharmacokinetic effects of different application sites showed no statistical differences in the serum concentrations of estradiol delivered between OESCLIM® applied to the buttock and OESCLIM® applied at three other sites [9]. Four different body sites were compared: arm, thigh, abdomen, and buttock and the results are shown in Fig. 6. This allows the patient a choice of application sites with the knowledge that the dose received will be consistent. It is interesting to note that OESCLIM® can be applied to the arm in addition to the buttock, thigh, and abdomen.
this as corresponding to a near maximum (94%) decrease in vasomotor symptoms compared to baseline [2]. Utian also reported that OESCLIM® was effective in highly symptomatic patients [11]. In a multi-centre, placebo controlled trial of 196 highly symptomatic menopausal women, OESCLIM® resulted in a significant decrease in vasomotor symptoms compared to placebo at all levels of dosage used (25, 50, or 100). The very good efficacy of OESCLIM® must be considered in view of the relationships between adhesion, tolerability and flux outlined in Fig. 1. If transdermal treatments are not well tolerated, either locally or systemically then patients will not be able to continue with treatment and gain relief from symptoms. OESCLIM® was developed to rise to this challenge.
7. Efficacy of OESCLIM®
8. Local skin tolerability
These smooth pharmacokinetic properties result in good efficacy and OESCLIM® has been shown to effectively reduce vasomotor symptoms in numerous trials, [2,10] even in highly symptomatic patients [11,12]. In an analysis of highly symptomatic patients (]5 vasomotor symptoms per day at baseline), the number of vasomotor symptoms per day had fallen from 10.096.3 at baseline, to only 0.6 9 1.6 when patients received OESCLIM® 50 (PB0.001). The authors reported
Local skin tolerability of HRT is important because it can affect a patient’s compliance and disrupt the balance between tolerability and efficacy needed to ensure an optimum delivery system. However, traditional transdermal systems have in the past been subject to problems causing local skin reactions including redness, spots, swelling, and even allergic reactions. The tolerability of OESCLIM® was assessed in four clinical trials with the total number of applications in
6. Influence of body site on pharmacokinetics and efficacy
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these trials being 25 837 [3,10 – 12]. Of these applications, the number of skin reactions was low at less than 5%. This good skin tolerability was found to be consistent across all four studies. OESCLIM® 50 was also compared to the reference transdermal patch, Estraderm TTS® 50 [3]. Both transdermal systems were designed to deliver 50 mg of estradiol per 24 h, and were applied to the upper part of the buttock, alternating the side of application. Treatment was administered according to a discontinuous cycle of 28 days, where patches were applied for the first 24 days, and followed by a 4 day treatment-free period. Local skin reactions in the OESCLIM® group were less than half those experienced with the reservoir
patch. Using OESCLIM®, only 4.2% of applications caused a site reaction (157 out of 3706 applications) compared to 9.5% in the Estraderm TTS® group (323 out of 3406 applications). This difference was statistically significant (PB0.001). The median duration of the reactions was found to be similar in each group at 24 h and the majority of reactions in both groups were reported to cause no discomfort or only slight discomfort. The degree of reactions causing considerable discomfort was 5.3% in the Estraderm TTS® group and only 3.8% in the OESCLIM® patients. However, none of the site reactions in the OESCLIM® group caused the patients to remove the patch prematurely.
Fig. 6. OESCLIM® average estradiol serum concentrations measured after application of OESCLIM® 50 to different body sites [9].
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10. Physical qualities and patient preference
Fig. 7. Total percentage of detachments (any reason). Reprinted from 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: 161–173, with permission from Elsevier Science.
9. Adhesion properties It is necessary for transdermal systems to remain adhered to the patient for the full duration of the treatment period in order to deliver the drug efficiently and effectively. If patches become detached then the patient will not receive optimum treatment. The adhesion of a transdermal patch is, therefore, a crucial factor for any HRT treatment because it can affect the pharmacokinetics of drug delivery if the full surface area of the patch does not remain in contact with the skin throughout the application period. Adhesion properties can also affect the compliance of a woman to her treatment regimen, if patches become detached early, or need to be removed because of poor adhesion. OESCLIM® has been tested in a range of clinical trials with over 25 000 applications. Of these, the rate of detachment was low at only 3 – 6% [2,10 –12]. In a trial comparing OESCLIM® 50 with Estraderm TTS® 50, the OESCLIM® group had fewer total detachments (6%) compared to 11% in the reservoir patch group (P B 0.001) (Fig. 7). It is interesting to note that in circumstances where patches may become detached because of water, (shower, bath) there was also a statistical significance between the two groups (P B0.001). A significance was also shown in the number of detachments because of dressing (P B0.001) [2].
The OESCLIM® system is a non-transparent, beige-colored patch, which was selected following a patient survey examining patient preferences for transdermal patches in four European countries. OESCLIM® is applied twice weekly onto the buttock, upper arm, abdomen, or thigh. Patient satisfaction is very important for any HRT because compliance is necessary in order to obtain all related benefits. Qualitative data obtained from women participating in long-term studies with OESCLIM®, indicate that the flexibility and comfort offered by the unique matrix design, are highly-attractive features resulting in high patient acceptability of treatment [12]. This qualitative data is backed up by the low drop-out rate seen in patients using OESCLIM® in clinical trials. In a randomized tolerability and efficacy study involving 283 patients, only one patient (0.7%) in the OESCLIM® 50 group dropped out because of a local site reaction. This compared to 7 patients (5.1%) who dropped out of the study when receiving Estraderm TTS® 50 (PB0.05). [3] (Fig. 8) It is also interesting to note that a recent longterm study of OESCLIM® conducted over 12 months found that 79% of women wished to continue with treatment at the end of the study period [12]. This statistic is in marked contrast to general compliance statistics which state that approximately 30% of patients never comply with treatment and that many patients who are started on HRT stop taking it within 9 months to 1 year [13].
11. Conclusion The transdermal route offers significant advantages over the oral route for the delivery of replacement estrogen because it avoids the hepatic first-pass effect and results in less deleterious metabolic changes. However, transdermal systems need to balance the adhesion, tolerability, and flux to ensure the optimum compliance with therapy which results in patient benefits.
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Fig. 8. Number of patients withdrawing from study because of local site reaction. Reprinted from 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: 175–185, with permission from Elsevier Science.
OESCLIM® is an innovative matrix patch specifically designed to overcome the problems of adhesion, skin tolerability, and acceptability currently associated with existing transdermal systems. The advanced pharmacokinetic profile of OESCLIM® means that physicians and patients can be confident that women will receive the correct dosage, delivered evenly across the treatment period, regardless of application site and patient variability. The favorable skin tolerability and very good adhesion properties of OESCLIM® mean that it has achieved a good balance between all three factors needed to improve the acceptability of transdermal therapies. OESCLIM® is a significant advance over existing therapy particularly in terms of tolerability and adhesion which means it can offer significant advantages to patients, which may prove useful in improving longterm compliance. In conclusion, OESCLIM® is a very good first-line choice for ERT and HRT which is suitable for most women.
References [1] Lievertz R. Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol 1987;156(51):1289–93. [2] Rozenbaum H, Birkhau¨ser M, De Nooyer C. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) I: tolerability, adhesion and efficacy. Maturitas 1996;25:161–73.
[3] Rozenbaum H, Birkhau¨ser M, De Nooyer C. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) II: local skin tolerability. Maturitas 1996;25:175 – 85. [4] Chetkowski RJ, Meldrum DR, Steingold KA. Biological effects of transdermal estradiol. N Engl J Med 1986;314:1615– 20. [5] Guichard JP, Sauron R, Dutertre JP. 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. [6] Laboratoires Fournier data on file. Surface proportionality study: A report on a comparative estradiol patch dose ranging study in 24 post menopausal women. Report K POE 91 01 KH 92 02, p. 67. [7] 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. [8] Laboratoires Fournier data on file. Pharmacokinetics of Oesclim® 50 after repeated applications over 3 weeks. Report KTS 17 93 02 KH 94 02, pp. 73 – 74. [9] Laboratoires Fournier data on file. Transdermal absorption of estradiol from a TS 17 estradiol transdermal system after application to four different body sites. Report KH TS 17 92 01 KH 93 02, p. 78. [10] Laboratoires Fournier data on file. Multicentre placebocontrolled clinical trial in parallel group carried out double-blind to evaluate the efficacy of 12 weeks treatment with TS 17 (22 cm2) on symptoms of estrogen deficiency caused by natural menopause. Report CTS 17 91 02 FR 95 02, pp. 194 – 196 and 242 – 245. [11] 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
A. Munoz / Maturitas 33 (1999) S39– S47 symptoms in highly symptomatic menopausal patients, Am J Obstet Gynecol 1999;181(1):71–79. [12] Taurelle R, L’Hermite M, Haenggi W, Lauritzen C, Studd JW. The long term tolerability and efficacy of
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OESCLIM®: results of a one-year study, Maturitas. 1999; 33 (Suppl. 1): S73 – S81. [13] Coope J, Marsh J. Can we improve compliance with long-term HRT? Maturitas 1992;15:151 – 8.
OESCLIM®: an advanced delivery system for HRT Alain Munoz * Laboratoires Fournier, 50 Rue de Dijon, 21121 Daix, France
Abstract Aims: Transdermal estradiol offers a number of advantages over traditional oral routes of hormone replacement therapy (HRT) because it is not subject to the hepatic first-pass effect. However, transdermal systems need to balance adhesion, tolerability, and flux if they are to be effective. OESCLIM® is a transdermal 17-b estradiol HRT system designed to address the problems of conventional transdermal patches and offer optimal adhesion and tolerability in an effective HRT system. This paper reviews some of the data on OESCLIM® with reference to its delivery system. Results: The innovative technology used in OESCLIM® results in a smooth pharmacokinetic profile throughout the 3–4 day application period. In recent pharmacokinetic studies, OESCLIM® 50 provided a more consistent release of hormone than Estraderm TTS® 50 and higher mean estradiol levels than Systen® and Vivelle®. This smooth pharmacokinetic profile is also maintained whether OESCLIM® is attached to different body sites. The local skin tolerability of OESCLIM® is good. One study reported that OESCLIM® 50 caused less than half the number of skin reactions as Estraderm TTS® 50 (4.2% compared to 9.5%). OESCLIM® has also been shown to have fewer detachments than Estraderm TTS® (6% compared to 11%). Both differences were statistically significant (PB 0.001). A study has shown OESCLIM® to be as effective as Estraderm TTS® at reducing vasomotor symptoms even in highly symptomatic women. Conclusion: OESCLIM® is a very good first-line choice for estrogen replacement therapy (ERT) or HRT providing effective therapy with optimum adhesion, flux and tolerability profiles. © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: HRT; OESCLIM®; Tolerability; Transdermal
1. Introduction The identification of an optimal delivery system for hormone replacement therapy (HRT) has been a concern for the medical profession since the introduction of the first estrogen replacement therapy over 50 years ago. During that time, a variety of systems have emerged with varying degrees of acceptability to patients and doctors. * Tel.: +33-380-447500; fax: + 33-380-447510.
These include oral preparations, transdermals, gels, injections, and subcutaneous implants. Transdermal administration offers a number of advantages over other more traditional oral routes. Orally-delivered estradiol (E2) is extensively metabolized in the gastro-intestinal tract to form a less active compound, estrone (E1). Estradiol delivered orally is subject to first-pass metabolism in the liver which reduces the estradiol levels available. The low bioavailability of oral estrogens means that oral routes of delivery
0378-5122/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 9 ) 0 0 0 6 2 - 6
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A. Munoz / Maturitas 33 (1999) S39– S47
require high initial doses to achieve therapeutic plasma levels. In addition, estrogens delivered orally can alter the synthesis of certain liver proteins [1]. Since the transdermal route avoids biological degradation because of the hepatic firstpass effect, it is possible to substantially reduce the dosage delivered compared to orals. A 40 – 80 fold lower dose of estradiol delivered transdermally can be used to achieve the same efficacy as orally-delivered estrogen. In addition, the transdermal route is more appropriate for certain types of patients than oral routes because they have less impact on hepatic metabolism and other risk factors such as high levels of triglycerides (e.g. diabetics, smokers, hypertriglyceridaemic patients). In order for a transdermal system to be effective, it must facilitate long term patient compliance by balancing three factors: adhesion, tolerability, and flux. (Fig. 1). An imbalance in any one of these factors may cause the system to fail overall. For example, if the flux of the drug is not sufficient, then the tolerability may be very good, but at the expense of efficacy. Similarly, if the adhesion is poor, then the system will again fail because it will become detached, disrupting the delivery of estrogen to the woman. Transdermal systems need to reach optimum levels of all three factors in order for the system to be acceptable to patients and their doctors. If this is achieved then transdermal systems offer the best first-line treatment for women seeking relief of vasomotor symptoms around the time of the menopause.
Fig. 1. Balance of factors needed for transdermal HRT delivery systems.
2. OESCLIM® OESCLIM® (ESCLIM®/ESCLIMA®) is a new transdermal 17-b estradiol preparation recently developed by Groupe Fournier. It was developed to address some of the problems associated with existing patches such as poor adhesion and local skin irritation. The patented matrix system used, is a significant advance in transdermal technology. It is foam backed, giving added comfort, and has a unique profile in the myriad of available HRT products [2,3]. It also differentiates OESCLIM® from other transdermal preparations available by offering optimum adhesion and tolerability profiles. OESCLIM® also offers effective therapy at lower doses than oral estrogen products, and its stable pharmacokinetic profile eliminates the peaks and troughs in plasma concentrations associated with oral routes [4]. These advances over oral and conventional transdermal products offer physicians the possibility of delivering real patient benefits.
3. Existing transdermal technology Conventional transdermal estrogen therapy was first introduced in 1985 and is still available today. First generation transdermal systems carried the hormones within a reservoir containing an alcoholic gel. The use of this carrier system was often associated with a local skin irritation at the site of application, such as redness and swelling. Early trials reported local side effects in 17–58% of patients. This relatively high proportion of reactions led to poor compliance amongst patients and resulted in approximately 8% of patients discontinuing therapy [3]. In these preparations, the drug is gradually discharged from the reservoir over the application period (Fig. 2). These systems are relatively rigid because of the need to contain the drug within the reservoir, and can have problems with adhesion, skin tolerability and comfort. And this imbalance between adhesion, tolerability and flux led to problems with patient acceptability.
A. Munoz / Maturitas 33 (1999) S39– S47
S41
ogy (Fig. 3). Its patented system delivers a natural human estrogen, 17-b estradiol, through a unique non-acrylic, beige-colored, self-adhesive matrix composition which provides very good patient comfort [Fig. 4]. The OESCLIM® matrix patch is composed of two layers: 1. the matrix system, and 2. a peelable bottom layer of siliconized polyester film which protects the face of the matrix until it is removed before application of OESCLIM® to the skin. The matrix system itself also consists of two layers. The layer attached to the skin is the ethylene vinyl acetate (EVA) matrix. This matrix
Fig. 2. Traditional transdermal reservoir system. Fig. 3. New generation matrix system.
A significant advance over conventional reservoir systems came with the development of matrix systems. In this type of system, the active ingredient is included in a polymer matrix. This is bound to a backing film which forms the exterior surface of the patch. The majority of transdermal systems currently available are acrylic matrix systems, and although their pharmacokinetic profile is more stable than reservoir systems, there are still problems with adhesion, skin tolerability, and comfort which need to be overcome if optimum performance is to be a reality. 4. Advanced transdermal technology of OESCLIM® OESCLIM® is the only transdermal HRT product to use an innovative new matrix technol-
Fig. 4. OESCLIM® matrix composition.
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contains the active compound 17-b estradiol, excipients and is self-adhesive. It controls the release of estradiol to the skin, and determines the adhesive properties of the system. This layer has good drug-delivery characteristics resulting in a smooth pharmacokinetic profile [5 – 7]. The EVA matrix uses high-quality components to provide optimal skin tolerability and does not use skin penetration enhancers which can be potentially irritative agents. The adhesives used have high cohesive properties to ensure optimal adhesion and easy removal of the system at the end of the application period, without leaving adhesive residues on the skin. The top layer of the patch consists of an alveolar foam backing, which protects the EVA matrix. The elastic properties of this unique foam backing make it extensible, soft, and flexible, allowing it to move with the skin, whilst staying firmly attached. The components of the OESCLIM® system, such as the beige color and advanced flexible backing, were developed after extensive research into women’s preferences for a transdermal system. Research was conducted across Europe to enable the development of a patch which would be widely accepted. Dose adaptation is important in successfully initiating HRT and in patient compliance as it allows physicians to tailor treatment to individual women. OESCLIM® is available in some countries, in five doses, delivering 25, 37.5, 50, 75, and 100 mg/24 h of estradiol. This allows great flexibility when titrating doses.
5. Pharmacokinetics of OESCLIM® The innovative technology used in the development of OESCLIM® has resulted in a stable pharmacokinetic profile. Estradiol is released from the EVA matrix by passive diffusion at a constant rate throughout the application period (3–4 days). This is because the concentration gradient of estradiol between the matrix and the skin remains constant during the absorption process. Estradiol is thus permanently supplied to the skin from the matrix.
Physiological serum levels of estradiol are reached 4 h after application and peak serum levels after 24 h. During the application of OESCLIM®, the estradiol/estrone serum concentrations ratio is close to 1, the physiological premenopausal value. There is no accumulation of estradiol, even after repeated doses of OESCLIM®. Estradiol serum levels decrease on removal of the patch, and serum concentrations return to baseline 8 h after removal of the patch [8]. In recent pharmacokinetic studies, OESCLIM® 50 provided a more consistent release of hormone than Estraderm TTS® 50 [6] and higher mean estradiol levels than Systen® [5]. When OESCLIM® 50 was compared to Estraderm TTS® 50, the area under curve (AUC) values were found to be approximately equivalent. However, the estradiol serum concentrations obtained with OESCLIM® were more stable over the 3–4 day application period. Fig. 5 shows the mean estradiol serum levels of the two systems, using two clinically-available doses of OESCLIM® [6]. One of the first matrix estradiol patches to be available in the United States was Vivelle®, known in Europe as Menorest®. When compared to this product in a randomized cross-over study involving 24 patients, OESCLIM® produced higher mean estradiol levels over 4 days of treatment. The good pharmacokinetic profile of OESCLIM® was also accompanied by better adhesion characteristics [7]. During repeated applications, the intra-subject variability was very low, at 2.5%. Low intra-subject variability is particularly important when considering adjusting a patient’s dose to aid compliance and reduce side effects, or when initiating treatment. The low variability between patients is amongst the lowest in commercially-available agents, in particular in comparison with oral products such as ethinyl estradiol. The new technology of OESCLIM® which is able to offer a predictable ratio of dose to serum estrogen concentration, means that physicians can be confident in adjusting treatment to suit individual patients.
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Fig. 5. Mean estradiol serum levels for 3-day application (24 women).
When using a transdermal patch, the site of application needs to be changed regularly to optimize local skin tolerance. Studies conducted on the pharmacokinetic effects of different application sites showed no statistical differences in the serum concentrations of estradiol delivered between OESCLIM® applied to the buttock and OESCLIM® applied at three other sites [9]. Four different body sites were compared: arm, thigh, abdomen, and buttock and the results are shown in Fig. 6. This allows the patient a choice of application sites with the knowledge that the dose received will be consistent. It is interesting to note that OESCLIM® can be applied to the arm in addition to the buttock, thigh, and abdomen.
this as corresponding to a near maximum (94%) decrease in vasomotor symptoms compared to baseline [2]. Utian also reported that OESCLIM® was effective in highly symptomatic patients [11]. In a multi-centre, placebo controlled trial of 196 highly symptomatic menopausal women, OESCLIM® resulted in a significant decrease in vasomotor symptoms compared to placebo at all levels of dosage used (25, 50, or 100). The very good efficacy of OESCLIM® must be considered in view of the relationships between adhesion, tolerability and flux outlined in Fig. 1. If transdermal treatments are not well tolerated, either locally or systemically then patients will not be able to continue with treatment and gain relief from symptoms. OESCLIM® was developed to rise to this challenge.
7. Efficacy of OESCLIM®
8. Local skin tolerability
These smooth pharmacokinetic properties result in good efficacy and OESCLIM® has been shown to effectively reduce vasomotor symptoms in numerous trials, [2,10] even in highly symptomatic patients [11,12]. In an analysis of highly symptomatic patients (]5 vasomotor symptoms per day at baseline), the number of vasomotor symptoms per day had fallen from 10.096.3 at baseline, to only 0.6 9 1.6 when patients received OESCLIM® 50 (PB0.001). The authors reported
Local skin tolerability of HRT is important because it can affect a patient’s compliance and disrupt the balance between tolerability and efficacy needed to ensure an optimum delivery system. However, traditional transdermal systems have in the past been subject to problems causing local skin reactions including redness, spots, swelling, and even allergic reactions. The tolerability of OESCLIM® was assessed in four clinical trials with the total number of applications in
6. Influence of body site on pharmacokinetics and efficacy
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these trials being 25 837 [3,10 – 12]. Of these applications, the number of skin reactions was low at less than 5%. This good skin tolerability was found to be consistent across all four studies. OESCLIM® 50 was also compared to the reference transdermal patch, Estraderm TTS® 50 [3]. Both transdermal systems were designed to deliver 50 mg of estradiol per 24 h, and were applied to the upper part of the buttock, alternating the side of application. Treatment was administered according to a discontinuous cycle of 28 days, where patches were applied for the first 24 days, and followed by a 4 day treatment-free period. Local skin reactions in the OESCLIM® group were less than half those experienced with the reservoir
patch. Using OESCLIM®, only 4.2% of applications caused a site reaction (157 out of 3706 applications) compared to 9.5% in the Estraderm TTS® group (323 out of 3406 applications). This difference was statistically significant (PB0.001). The median duration of the reactions was found to be similar in each group at 24 h and the majority of reactions in both groups were reported to cause no discomfort or only slight discomfort. The degree of reactions causing considerable discomfort was 5.3% in the Estraderm TTS® group and only 3.8% in the OESCLIM® patients. However, none of the site reactions in the OESCLIM® group caused the patients to remove the patch prematurely.
Fig. 6. OESCLIM® average estradiol serum concentrations measured after application of OESCLIM® 50 to different body sites [9].
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10. Physical qualities and patient preference
Fig. 7. Total percentage of detachments (any reason). Reprinted from 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: 161–173, with permission from Elsevier Science.
9. Adhesion properties It is necessary for transdermal systems to remain adhered to the patient for the full duration of the treatment period in order to deliver the drug efficiently and effectively. If patches become detached then the patient will not receive optimum treatment. The adhesion of a transdermal patch is, therefore, a crucial factor for any HRT treatment because it can affect the pharmacokinetics of drug delivery if the full surface area of the patch does not remain in contact with the skin throughout the application period. Adhesion properties can also affect the compliance of a woman to her treatment regimen, if patches become detached early, or need to be removed because of poor adhesion. OESCLIM® has been tested in a range of clinical trials with over 25 000 applications. Of these, the rate of detachment was low at only 3 – 6% [2,10 –12]. In a trial comparing OESCLIM® 50 with Estraderm TTS® 50, the OESCLIM® group had fewer total detachments (6%) compared to 11% in the reservoir patch group (P B 0.001) (Fig. 7). It is interesting to note that in circumstances where patches may become detached because of water, (shower, bath) there was also a statistical significance between the two groups (P B0.001). A significance was also shown in the number of detachments because of dressing (P B0.001) [2].
The OESCLIM® system is a non-transparent, beige-colored patch, which was selected following a patient survey examining patient preferences for transdermal patches in four European countries. OESCLIM® is applied twice weekly onto the buttock, upper arm, abdomen, or thigh. Patient satisfaction is very important for any HRT because compliance is necessary in order to obtain all related benefits. Qualitative data obtained from women participating in long-term studies with OESCLIM®, indicate that the flexibility and comfort offered by the unique matrix design, are highly-attractive features resulting in high patient acceptability of treatment [12]. This qualitative data is backed up by the low drop-out rate seen in patients using OESCLIM® in clinical trials. In a randomized tolerability and efficacy study involving 283 patients, only one patient (0.7%) in the OESCLIM® 50 group dropped out because of a local site reaction. This compared to 7 patients (5.1%) who dropped out of the study when receiving Estraderm TTS® 50 (PB0.05). [3] (Fig. 8) It is also interesting to note that a recent longterm study of OESCLIM® conducted over 12 months found that 79% of women wished to continue with treatment at the end of the study period [12]. This statistic is in marked contrast to general compliance statistics which state that approximately 30% of patients never comply with treatment and that many patients who are started on HRT stop taking it within 9 months to 1 year [13].
11. Conclusion The transdermal route offers significant advantages over the oral route for the delivery of replacement estrogen because it avoids the hepatic first-pass effect and results in less deleterious metabolic changes. However, transdermal systems need to balance the adhesion, tolerability, and flux to ensure the optimum compliance with therapy which results in patient benefits.
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Fig. 8. Number of patients withdrawing from study because of local site reaction. Reprinted from 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: 175–185, with permission from Elsevier Science.
OESCLIM® is an innovative matrix patch specifically designed to overcome the problems of adhesion, skin tolerability, and acceptability currently associated with existing transdermal systems. The advanced pharmacokinetic profile of OESCLIM® means that physicians and patients can be confident that women will receive the correct dosage, delivered evenly across the treatment period, regardless of application site and patient variability. The favorable skin tolerability and very good adhesion properties of OESCLIM® mean that it has achieved a good balance between all three factors needed to improve the acceptability of transdermal therapies. OESCLIM® is a significant advance over existing therapy particularly in terms of tolerability and adhesion which means it can offer significant advantages to patients, which may prove useful in improving longterm compliance. In conclusion, OESCLIM® is a very good first-line choice for ERT and HRT which is suitable for most women.
References [1] Lievertz R. Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol 1987;156(51):1289–93. [2] Rozenbaum H, Birkhau¨ser M, De Nooyer C. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) I: tolerability, adhesion and efficacy. Maturitas 1996;25:161–73.
[3] Rozenbaum H, Birkhau¨ser M, De Nooyer C. Comparison of two estradiol transdermal systems (OESCLIM® 50, ESTRADERM TTS® 50) II: local skin tolerability. Maturitas 1996;25:175 – 85. [4] Chetkowski RJ, Meldrum DR, Steingold KA. Biological effects of transdermal estradiol. N Engl J Med 1986;314:1615– 20. [5] Guichard JP, Sauron R, Dutertre JP. 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. [6] Laboratoires Fournier data on file. Surface proportionality study: A report on a comparative estradiol patch dose ranging study in 24 post menopausal women. Report K POE 91 01 KH 92 02, p. 67. [7] 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. [8] Laboratoires Fournier data on file. Pharmacokinetics of Oesclim® 50 after repeated applications over 3 weeks. Report KTS 17 93 02 KH 94 02, pp. 73 – 74. [9] Laboratoires Fournier data on file. Transdermal absorption of estradiol from a TS 17 estradiol transdermal system after application to four different body sites. Report KH TS 17 92 01 KH 93 02, p. 78. [10] Laboratoires Fournier data on file. Multicentre placebocontrolled clinical trial in parallel group carried out double-blind to evaluate the efficacy of 12 weeks treatment with TS 17 (22 cm2) on symptoms of estrogen deficiency caused by natural menopause. Report CTS 17 91 02 FR 95 02, pp. 194 – 196 and 242 – 245. [11] 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
A. Munoz / Maturitas 33 (1999) S39– S47 symptoms in highly symptomatic menopausal patients, Am J Obstet Gynecol 1999;181(1):71–79. [12] Taurelle R, L’Hermite M, Haenggi W, Lauritzen C, Studd JW. The long term tolerability and efficacy of
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OESCLIM®: results of a one-year study, Maturitas. 1999; 33 (Suppl. 1): S73 – S81. [13] Coope J, Marsh J. Can we improve compliance with long-term HRT? Maturitas 1992;15:151 – 8.