Elsevier

Maturitas

Volume 34, Issue 1, 15 January 2000, Pages 47-55
Maturitas

Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX®) in postmenopausal women

https://doi.org/10.1016/S0378-5122(99)00085-7Get rights and content

Abstract

Objective: To examine the efficacy and tolerability of a new matrix patch delivering estradiol (E2 Matrix) at doses of 0.05 and 0.10 mg per day (Estraderm MX® 50, 100) in the treatment of moderate to severe postmenopausal symptoms. Methods: A total of 254 postmenopausal women were randomized to receive treatment with E2 Matrix 0.10 mg (N=86), E2 Matrix 0.05 mg (N=82), or placebo (N=86) in a double-blind, double-dummy fashion for a period of 12 weeks continuously. Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times. The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment. Other efficacy variables included reduction in hot flushes at 4 and 8 weeks, reduction in daytime flushing and night sweats, and Kupperman Index at 4, 8, and 12 weeks. Results: E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4, 8, and 12 weeks of treatment (P<0.001). Also, for all other efficacy parameters studied, both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points (P<0.001). Local tolerability was good in both groups. A slight increase in estrogen related adverse effects (breast tenderness, leukorrhoea) was seen with the 0.10 mg patch. Adhesion of patches and compliance were good. Overall systemic tolerability was good in both treated groups. However, a 4.8% overall incidence of endometrial hyperplasia was observed in patients with an intact uterus. Conclusions: This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day. It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems. In light of the observed hyperplasia after treatment in five patients, estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus.

Introduction

Transdermal hormonal replacement therapy is well established as an effective treatment of the sequelae of estrogen deficiency occurring after natural and surgical menopause [1], [2]. The transdermal route of administration avoids the hepatic first pass metabolism occurring with oral estrogens and therefore offers the opportunity to maintain physiological levels of estradiol with very low daily doses [1], [3]. Furthermore, with oral administration, high concentrations of estrogen in hepatic sinusoids stimulate the synthesis of several hepatic proteins resulting in increases in clotting factors and renin substrates, which are considered undesirable [4].

Estraderm TTS® has been available for several years for the administration of the physiological estrogen, estradiol, through the skin at a constant rate for up to 4 days. The delivery system is a reservoir patch, which contains small amounts of alcohol as a flux enhancer. Estraderm TTS® is well established as an effective, safe and well tolerated preparation for the treatment of postmenopausal women [1], [2], [3]. However, in a small minority of women, the alcohol component may cause skin irritation, which can lead to discontinuation of therapy in approximately 6% of patients [2], [3], [5], [6]. Matrix patches, devoid of alcohol, have recently been developed [7], [8], [9], [10], [11]. In these systems the estradiol is contained within the adhesive component itself. The overall skin tolerability of estradiol matrix patches appears to be similar to that of existing Estraderm TTS®. However, for women with sensitivity to alcohol they may represent an advance. They have also been reported to have stronger adhesion [7]. The literature contains several studies examining the safety and efficacy of a variety of such matrix patches in postmenopausal women [8], [9], [10], [11]. In the majority of these cases, the patches described deliver approximately 0.05 mg of estradiol per day.

The new transdermal patch described in the current study was developed to provide a matrix system delivering estradiol (E2 Matrix) at bioequivalent doses to existing Estraderm TTS® 50 and 100. The 22-cm2 patch applied in the study has a nominal delivery of 0.05 mg, and the 44-cm2 patch of 0.10 mg of estradiol per day. The study reported here examines the efficacy, and the systemic and local tolerability, of this new matrix system (Estraderm MX® 50 and 100) in the treatment of moderate to severe hot flushes.

Section snippets

Patients

Healthy postmenopausal female outpatients, with or without previous hormone replacement therapy (HRT), requiring treatment for climacteric symptoms, were eligible to participate in the study. Patients were required to be at least 8 months after last spontaneous menstrual bleeding or 6 weeks post-oophorectomy, and to have experienced a mean number of seven or more moderate to severe hot flushes (including night sweats) per 24 h in the 14 days prior to randomization. In addition, all patients had

Patients

A total of 254 patients were randomized, 86 to E2 Matrix 0.10 mg, 82 to E2 Matrix 0.05 mg, and 86 to placebo. All patients were in the age range 40–64 years. All patients except three in the E2 Matrix 0.10-mg group were Caucasian. Table 1 shows that there were no differences between the groups with respect to demographics or baseline data.

Of the 254 randomized patients, 227 patients completed the study. Of the 27 patients who discontinued prematurely, six patients discontinued due to poor

Conclusions

This represents the first reported study examining the efficacy and tolerability of a new matrix system delivering estradiol transdermally at doses of 0.05 and 0.10 mg in the treatment of moderate to severe postmenopausal symptoms. The data show this new E2 Matrix to be highly effective in relieving hot flushes at both dose strengths studied, with significant reductions at 4, 8 and 12 weeks compared to placebo. The study also demonstrates both dosage forms to be highly effective in reducing

Acknowledgements

We would like to acknowledge the collaboration and commitment of all the local investigators and their staff, L.G.M. Mulders, St. Doetinchemse Ziekenhuizen, Doetinchem, F.M. Helmerhorst, University Hospital Leiden, P.C. Scholten, Diakonessenhuis Utrecht, A.P.E. Schmoutziguer, Rijnstate Ziekenhuis Arnhem, P. van de Weg, Ziekenhuis Gelderse Vallei, Ede and A. Verhoeff, Zuiderziekenhuis, Rotterdam without whom the present study would not have been possible. We also thank E. Peruzzi, Biol Sci for

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