Abstract
This article describes a novel transdermal estradiol spray developed for the treatment of menopausal vasomotor instability. The spray delivers estradiol directly into the subcutaneous microcirculation achieving the advantages of estradiol patches, creams and gels but with minimal skin reaction, patient inconvenience or cosmetic shortcomings associated with transdermal methods. In the one published Phase III clinical trial, postmenopausal women (n = 454) with eight or more moderate-to-severe hot flashes per day applied each morning, one, two or three estradiol 90 μl sprays (each containing estradiol 1.53 mg) versus matching placebo sprays. There was a significant decrease in hot flash frequency and intensity at weeks 4 and 12 compared with corresponding placebo groups (p < 0.010). The systemic estradiol delivery rates at week 12 were approximately 0.021, 0.029 and 0.040 mg/day for the 1-, 2- and 3-spray doses, respectively. There were common adverse events similar to those previously reported with transdermal estradiol, except for skin irritation, which was very low. The spray is a well-tolerated, cosmetically attractive and convenient method of delivering low-dose, transdermal estradiol.
This article describes the rationale for and evaluates early experience with a transdermal estradiol spray (Evamist®, Ther-Rx Corporation, MO, USA) that was recently introduced and approved for clinical use in the USA by the US FDA. There is only a single (evidence level 1) clinical trial documenting the efficacy of this therapy. This review will focus heavily on that report [1].
This estradiol spray was developed because existing transdermal estradiol delivery systems have shortcomings that discourage their widespread use, even though they provide major advantages over oral delivery [1–7]. Skin patches, the traditional system for transdermal delivery, have resulted in skin irritation and patch adhesion problems [3]. Estradiol patches, gels and lotions are objectionable to some because they peel off from adhesive failures, catch on clothing, irritate skin and induce allergies [4–7]. Some women find patches unsightly because they soil after days of wear. Others consider gels and lotions messy and object to the finger contact in dispersing the medication [4–7].
Transdermal systems transfer bioactive hormone directly into the subcutaneous microcirculation where steroid delivery is a close simulation of natural estradiol secretion. There is no first-pass hepatic transformation or deactivation of the dosed estradiol [2,3]. Transdermal estradiol has little or no effect on clotting factors, lipoproteins, sex hormone-binding globulin (SHBG), hepatic enzymes or C-reactive protein [2,3]. Not unexpectedly, recent reports have shown little or no increase in thromboembolic events with transdermal estradiol compared with oral estrogens [8–10]. Transdermal systems deliver therapeutic circulating estradiol levels and demonstrate clinical efficacy for hot flashes at doses considerably lower than those reported with oral estrogens, probably because there is less interconversion into estrone and estrone sulfate pools [2,3]. Transdermal estradiol delivery better simulates the circulating profiles of estradiol, estrone and estrone sulfate normally observed in follicular phase premenopausal women than do oral systems [2]. Clinical consensus with respect to vasomotor symptoms stipulates lowest possible estrogen dosing for the shortest time [11–16]. It appears that transdermal estradiol is currently the best strategy to meet the ‘lowest dose possible’ standard [11–16].
Overview of the market
In the USA, approximately 37 million women are at or near menopause with some 45.5 million beyond menopause. Up to 75% of the women experience vasomotor symptoms during the perimenopausal transition or after menopause. Vasomotor symptoms are a significant quality of life and workplace issue because substantial numbers of these women experience symptoms that are debilitating [17,18]. Although estrogens are the most effective agent available for suppression of vasomotor symptoms, their use in the USA became sharply curtailed after 2002 with concerns about breast cancer and cardiovascular events associated with oral estrogens and doses in use at that time [19].
The compound & its chemistry
The active agent is chemically identical to the naturally occurring estradiol [1]. Estradiol is the principal estrogen secreted by the human ovary in healthy premenopausal women. Estradiol is delivered in a push button applicator that contains a homogeneous solution of estradiol USP (17-β-estradiol), octisalate and alcohol (ethanol 95%). One estradiol spray delivers 90 μl containing estradiol 1.53 mg. The application area (20 cm2 per spray) is controlled by a plastic housing, which directs the distance and angle of the spray from the skin surface providing reproducible application of the solution to a specified area [1]. Estradiol in ethanol is mixed with a skin-penetrating agent, octisalate, which binds the estradiol, penetrates the dermal layers of skin and then releases estradiol into the microcirculation at a steady rate over 24 h before it declines [1]. Dosing of one, two or three sprays is selected by the user as the lowest number of sprays required to control vasomotor symptoms.
Pharmacokinetics & metabolism
This spray delivers estradiol directly into the microcirculation of the skin using a precisely metered spray [1]. The volume is 90 μl, and its variability is approximately 10% [1]. The Phase III clinical trial measured estradiol, estrone and estrone sulfate serum levels by HPLC for all participants at baseline and at weeks 4, 8 and 12 of treatment. These samples, drawn during daytime between 2 and 6 h postdosing, provided a reasonable estimate of the average concentration of each analyte during the daily dosing cycle. Increases in estradiol were observed with levels of 30.7 (24.1, 39.1) pg/ml to 40.1 (32.6, 49.4) pg/ml observed in the three-spray group. In the two-spray group, mean serum estradiol levels ranged between 24.0 (18.6, 31.0) pg/ml and 32.1 (24.7, 41.8) pg/ml [1]. Mean estradiol levels of 19.5 (15.3, 25.0) pg/ml to 22.9 (17.9, 29.3) pg/ml were observed in the one-spray group [1]. The amount of estradiol delivered to the systemic circulation was estimated by multiplying the average steady state baseline adjusted estradiol levels in serum (pg/ml) by the clearance rate of estradiol in postmenopausal women (l/day) by 1000 [1]. Using the clearance rate of approximately 13.1 ml/kg/min (or 1350 l/day) and the estradiol serum values from the study, the systemic delivery rates were approximately 0.021 mg/day, 0.029 mg/day and 0.040 mg/day of estradiol for the one-, two- and three-spray doses, respectively. The estradiol-treated women had an overall mean serum estrone level of 42.2 pg/ml and mean estrone sulfate level of 772.9 pg/ml at week 12 [1].
Clinical efficacy
There has been one Phase III trial describing clinical efficacy of the estradiol spray [1]. This report was a randomized, double-blind, placebo-controlled, parallel-group clinical trial conducted at 43 sites in the USA [1]. There were three study periods (4-week baseline evaluation, 12-week treatment and 4–6 week follow-up) and six study visits. Participants were naturally or surgically postmenopausal women aged 35 years or older who were healthy with an average of at least eight moderate-to-severe hot flashes per day (≥56 per week) [1]. Subjects recorded in a daily diary the number and severity (0, none; 1, mild; 2, moderate; or 3, severe) of hot flashes during the 4-week baseline evaluation period. Eligible subjects were randomized to one of the six treatment groups: one, two or three sprays of estradiol or placebo administered transdermally once-daily to the inner forearm using a metered-dose pump. For women with an intact uterus, a daily dose of medroxyprogester-one acetate (MPA) 5 or 10 mg was prescribed for 2 weeks after the end of the 12-week treatment period [1].
The coprimary efficacy end points were mean change from baseline in frequency and severity of moderate-to-severe hot flashes at weeks 4 and 12 of treatment [1].
Safety and tolerability were evaluated by tabulation of adverse events (AEs): local skin tolerability; vital signs; physical examination (hematology, blood chemistry and urinalysis); coagulation factors; lipid profile; pap test; spontaneous vaginal bleeding; endometrial status (as determined by endometrial biopsy at screening and at end of study medication treatment, prior to MPA dosing); and SHBG [1].
For the primary efficacy end points, the mean change in frequency and severity of moderate-to-severe hot flashes from baseline to weeks 4 and 12 were compared between the treatment groups using the analysis of covariance model [1]. Frequency counts were used to evaluate subject assessment of treatment effect. The demographic and other baseline characteristic tests for treatment differences used analysis of variance (ANOVA) for continuous variables and Fisher's exact test for categorical variables. AEs, laboratory parameters and physical examination results were evaluated by descriptive statistics [1]. Statistical tests to evaluate treatment differences were two-sided with a significance level of 5% (α = 0.05) and were declared statistically significant if the calculated p-value was less than or equal to 0.05 [1]. The results of this trial are summarized below [1].
The reduction in the frequency of moderate-to-severe hot flashes was statistically significant for all three estradiol dose levels at weeks 4 and 12 [1]. In the three-spray estradiol group, the frequency decreased from 10.78 ± 3.58 flashes/day at baseline to 4.14 ± 3.10 flashes/day at week 4, a change of −6.64 ± 4.23 flashes/day. This was significantly greater (p < 0.001) than the change observed in the placebo group (−4.54 ± 7.40). At week 12, the change was also significantly greater (p < 0.001) in women treated with three-spray estradiol (−8.44 ± 4.50) than those on placebo (−5.32 ± 6.30). A −7.30 ± 6.93 decrease was noted at week 4 in the two-spray estradiol group compared with −4.74 ± 4.38 in placebo (p = 0.003). Similarly, a significant decrease (p = 0.010) in frequency was reported at week 12 (estradiol: −8.66 ± 6.65; placebo: −6.19 ± 5.77). Reductions were significantly different between the one-spray estradiol group and placebo at weeks 4 (−6.26 ± 4.01 vs −3.64 ± 5.30; p = 0.001) and 12 (−8.10 ± 4.02 vs −4.76 ± 5.84; p < 0.001) [1]. The weekly data showed that differences between estradiol and placebo in the change in frequency of moderate-to-severe hot flashes became statistically significant (p < 0.050) relative to placebo by week 2 in all dose groups. By week 4, the difference in hot flash frequency between estradiol and placebo exceeded two per day in all dose groups; the difference was maintained or increased in the subsequent weeks [1].
Significant reductions (p < 0.050) in the severity score of moderate-to-severe hot flashes was observed in the three-spray and two-spray estradiol groups at both weeks 4 and 12 [1]. The baseline severity score (2.58 ± 0.25) was reduced to 2.15 ± 0.73 at week 4 and 1.50 ± 1.06 at week 12 in the three-spray estradiol group. This change (week 4: p = 0.003; week 12: p < 0.001) was significantly greater than the three-spray placebo group (baseline: 2.54 ± 0.24; week 4: 2.41 ± 0.58; week 12: 2.23 ± 0.79). The baseline severity score (2.54 ± 0.21) was reduced to 1.97 ± 0.87 at week 4 and 1.63 ± 1.07 at week 12 in the two-spray estradiol group. These levels (p = 0.016 and p = 0.041, respectively) were significantly improved relative to placebo (week 4: 2.29 ± 0.71; week 12: 2.00 ± 0.96). The change in severity score at week 12 (−1.04 ± 1.01) was significantly greater (p < 0.001) in the one-spray estradiol group than in the one-spray placebo group (−0.26 ± 0.60) and trended toward significance at week 4 (p = 0.057) [1]. A significant (p < 0.050) reduction in hot flash severity score was first achieved at weeks 3, 4 and 5 in the three-, two- and one-spray estradiol groups relative to placebo, respectively [1]. The difference was sustained throughout the 12-week study period in all doses [1].
Postmarketing surveillance
The only estradiol spray currently available has been on the market in the USA for less then 1 year. No postmarketing information is yet available.
Safety & tolerability
In the Phase III trial cited in this report, AEs were reported in 129 (57.1%) women on estradiol and 114 (50.0%) women on placebo [1]. At least one adverse reaction was reported by 60.5, 55.4 and 55.3% of women in the three-, two- and one-spray estradiol treatment groups, respectively, and by 50.7, 53.9 and 45.5% of women in the three-, two- and one-spray placebo groups, respectively [1]. Headache was the most frequently reported AE. The most commonly reported events are known effects of estradiol treatment. Treatment-related application site events were reported in three (1.3%) women on estradiol and in four (1.8%) women on placebo. A total of 12 women (2.6%) withdrew from the study as a result of an AE; (six: estradiol; six: placebo). Nine serious AEs were reported in eight women (seven: estradiol; one: placebo); all were assessed as not related to study medication. There were no deaths, no pulmonary emboli, venous thromboemboli, myocardial infarctions or strokes reported [1].
Application-site erythema was evaluated. The mean erythema score ranged from no erythema to very slight (barely perceptible) erythema [1].
A single abnormal endometrial biopsy, simple hyperplasia without atypia, was identified in the two-spray estradiol group at the end of treatment (before MPA dosing). The follow-up biopsy performed six months after end of treatment was reported by the site as atrophic [1].
Regulatory affairs
The estradiol spray was approved by the US FDA and became available for clinical use in 2008 in the USA [101]
Conclusion
The new estradiol spray significantly reduces frequency and severity of moderate-to-severe hot flashes in menopausal women [1]. A significant decrease in frequency was already evident on the second week of treatment for all the three doses and was sustained throughout the 12 weeks of treatment. Estradiol spray achieved efficacy at 0.021–0.040 mg/day delivery rates. Currently, the lowest effective transdermal patch indicated to treat vasomotor symptoms is 0.025 mg/day; the lowest dose delivered for a transdermal estradiol gel is approximately 0.012 mg/day [5].
The spray has unique features that are expected to increase patient acceptability over earlier transdermal systems [1]. The spray goes on clear, dries in 60 s, becomes undetectable and has low skin irritation. The solvent is ethanol containing a skin-penetrating agent, octisalate which facilitates incorporation of steroid below the skin's surface where it is retained in a depot that delivers slow release of estradiol over a 24 h period [1]. The spray delivers a precisely metered dose of estradiol to the ventral surface of the forearm, does not require a patch and is touchless since there is no hand contact with the medication [1]. It does not wash off or transfer to other people when appropriate restrictions are followed, which include waiting for 30 min before washing or allowing other people to touch the application area. Finally, the spray is minimally affected by sunscreen, after which it still continues to deliver estradiol [1].
Executive summary
Estrogens are the most effective therapy available for suppression of vasomotor symptoms in menopausal women.
Transdermal estradiol delivered directly into the microcirculation is a close simulation of endogenous secretion.
Estradiol patches, gels and lotions are objectionable because they peel off, catch on clothing, irritate skin, induce allergies, accumulate dirt, are messy and require finger contact.
This estradiol spray was developed as an improvement over existing transdermal estradiol-delivery systems.
In the USA, approximately 37 million women are at or near menopause.
Up to 75% of the women experience vasomotor symptoms during the perimenopausal transition or after menopause.
Vasomotor symptoms are a significant quality of life and workplace issue because substantial numbers of these women experience symptoms that are debilitating.
The active agent is chemically identical to naturally occurring estradiol.
Estradiol in ethanol is mixed with a skin-penetrating agent, octisalate, which binds the estradiol, penetrates the dermal layers of skin and then releases estradiol into the microcirculation at a steady rate over 24 h before it declines.
The spray goes on clear, dries in 60 s and becomes undetectable.
This spray delivers estradiol directly into the microcirculation of the skin using a precisely metered spray.
Using the clearance rate of approximately 13.1 ml/kg/min (or 1350 l/day) and the estradiol serum values from the study, the systemic delivery rates were approximately 0.021 mg/day, 0.029 mg/day and 0.040 mg/day of estradiol for the one-, two- and three-spray doses, respectively.
The spray significantly reduces frequency and severity of moderate-to-severe hot flashes in menopausal women.
No information available yet.
Nine serious adverse events were reported in eight women (seven: estradiol; one: placebo); all were assessed as not related to study medication.
There were no deaths, no pulmonary emboli, venous thromboemboli, myocardial infarctions or strokes reported.
The mean erythema score ranged from no erythema to very slight (barely perceptible) erythema.
A single abnormal endometrial biopsy, simple hyperplasia without atypia, was identified in the two-spray estradiol group at the end of treatment (before medroxyprogesterone acetate dosing). The follow-up biopsy performed 6 months after end of treatment was reported by the site as atrophic.
The estradiol spray (Evamist®) has been approved by the US FDA, and is now available for clinical use.
This estradiol ‘spray-on patch’ is a novel treatment option for women who will benefit from the advantages of transdermal estradiol delivery but are intolerant of or are not inclined to use patches, gels or emulsions.
The spray is well-tolerated, cosmetically attractive, convenient and is expected to be a first choice for transdermal estradiol delivery for many women.
Transdermal delivery facilitates suppression of vasomotor symptoms with doses far lower than required with oral estrogens.
The one Phase III trial cited in this review supports the efficacy and safety of the first transdermal estradiol spray approved in the USA for the treatment of moderate-to-severe vasomotor symptoms in healthy menopausal women [1]. The dose regimen starts with one spray per day and can be increased to a maximum of three sprays per day in women for whom higher estradiol levels may be necessary to achieve an acceptable reduction in vasomotor symptom frequency. The addition of this novel estradiol spray to the current armamentarium of estradiol therapies allows for a low dose of estradiol as endorsed by clinical and regulatory authorities, with the added flexibility of dose titration as needed.
Future perspective
Transdermal estradiol is likely to become increasingly popular in the USA where there continues to be concern regarding oral estrogens, first-pass metabolism and the philosophy of lowest dose possible. This estradiol ‘spray-on patch’ is a novel treatment option for women who will benefit from the advantages of transdermal estradiol delivery but are intolerant of or are not inclined to use patches, gels or emulsions. For many users, the spray will be an attractive first choice for transdermal estradiol delivery.
Information resources
The estradiol spray has been described in a single Phase III clinical trial.
Footnotes
John E Buster received grants from Vivus Incorporated paid through the Baylor College of Medicine to perform clinical studies on Evamist. John E Buster also received hourly fees as a technical consultant from both Vivus (earlier studies) and Ther-Rx (later studies) and was sponsored by Vivus for giving speaking engagements. John E Buster has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.