Why the product labeling for low-dose vaginal estrogen should be changed

This commentary summarizes the activities of several clinicians and researchers to encourage modifications to the labeling of low-dose vaginal estrogen. Motivated by concerns of practicing clinicians that the boxed warning on the labels and package inserts for these products overstate potential risks and thus adversely affect patient care, leaders in the field are spearheading an effort to encourage consideration of alternative labeling, as discussed below. The members of the Working Group on Women’s Health and Well-Being in Menopause have affiliations with a number of medical societies, including The North American Menopause Society, the American College of Obstetricians and Gynecologists, the Endocrine Society, the American Society for Reproductive Medicine, the International Society for the Study of Women’s Sexual Health, and other professional organizations. We appreciated the opportunity to share our concerns, literature review, and proposal for alternative labeling with members of the US Food and Drug Administration (FDA) Division of Bone, Reproductive, and Urologic Products via a teleconference earlier this year. We encourage further consideration of our rationale and proposal by both the FDA and the pharmaceutical companies that own these products. Overview of the proposal for label change Vulvovaginal atrophy (VVA; also known as genitourinary syndrome of menopause) is a common and progressive condition that adversely affects the health and quality of life of many postmenopausal women. 1 Symptomatic VVA is a growing problem because of the confluence of several factors, including the burgeoning population of older postmenopausal women and the declining use of systemic menopausal hormone therapy since the initial report of the Women’s Health Initiative (WHI). 2, 3 Our view is that an additional factor—the boxed warning on the package label for low-dose vaginal estrogen—discourages clinicians from prescribing the product and women from taking it even after purchase. The boxed warning, which reflects estrogen class labeling, states “WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER, and PROBABLE DEMENTIA” and is based on extrapolations of data from clinical trials of systemic hormone therapy such as the WHI, which involved substantially higher levels of exposure. We believe that the boxed warning is not evidence-based and harms women by discouraging the use of a highly effective local treatment of a common condition with medical risks and adverse effects on quality of life. We contend that the boxed warning for low-dose vaginal estrogen products is unjustified based on several lines of reasoning described below, including the following: (a) the dramatic differences in blood hormone levels achieved by low-dose vaginal estrogen (eg, Vagifem tablets estradiol 10 μg, Estring releasing estradiol 7. 5 μg/d, or comparable low-dose vaginal estrogen cream formulations) versus conventional systemic estrogen therapy; (b) absence of randomized trial evidence or consistent observational evidence linking low-dose vaginal estrogen to cancer, cardiovascular disease, dementia, or any of the other conditions highlighted in the boxed warning; and (c) absence of evidence that changes in blood hormone levels—of the small magnitude achieved with these products—increase risk of these conditions. As a result of the boxed warning, a large number of older women with symptomatic VVA and genitourinary symptoms are being undertreated and do not receive the substantial benefits that these medications could provide. We believe that women would be better served by a modified label that more closely reflects the safety profile of low-dose vaginal estrogen and would actually enhance safety by emphasizing the key information that women and clinicians need to know about the products. Our proposal is to state in the package labeling, in regular text and font, that estrogen and estrogen-progestin given systemically, in higher doses, have been linked to the health conditions currently noted in the boxed warning, but that the relevance to low-dose vaginal estrogen remains unknown, given minimal increase in serum estrogen levels with low-dose vaginal estrogen products. We recommend bolding the phrase “report any vaginal bleeding or spotting right away while using ______. ” We also recommend adding in bold “Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product. ” We believe that these label changes will, paradoxically, enhance patient safety because the relevant information and cautions will stand out and be highly visible, rather than being obscured by extraneous and alarming bolded and boxed statements that lack proven relevance to the product. Thus, the proposed label change would serve the purpose of informing women of previous research and addressing safety issues while stating that the relevance of past research findings on systemic hormone therapy to low-dose vaginal estrogen is unknown. The specific suggested wording of our proposed label change is provided at the end of this commentary. Prevalence of VVA (Genitourinary Syndrome of Menopause) and the impact on women’s health and quality of life VVA symptoms, such as vaginal dryness, lack of lubrication, pain or spotting with intercourse, and burning with urination, affect 20% to 45% of midlife and older women. 4, 5 In contrast to vasomotor symptoms, which tend to improve across time irrespective of treatment, VVA is usually progressive and unlikely to resolve without intervention. VVA symptoms can have a significantly adverse effect on a woman’s sexual health and quality of life. In an online survey conducted in six countries, an estimated 45% of postmenopausal women reported experiencing vaginal symptoms. 6 The largest survey of US women, REVIVE (Real Women’s Views of Treatment Options for Menopausal Vaginal Changes), included 3, 046 women with VVA symptoms. 7 In this study, 85% of women with partners reported “some loss of intimacy, ” 59% indicated that VVA symptoms detracted from enjoyment of sex, 47% of women with partners reported that VVA interfered with their relationship, and 27% reported that VVA had a negative effect on their general enjoyment of life. Similar results were found in the VIVA (Vaginal Health: Insights, Views nonetheless, clinical studies demonstrate that a substantial proportion of women are undertreated. 1 Moreover, in our collective clinical experience and in those of the professional colleagues we represent, among women who seek treatment and/or receive prescriptions for low-dose vaginal estrogen, a substantial proportion ultimately choose not to use the product or discontinue use because of concerns and alarm about the boxed warning in the package insert. Testimonials by working group members during the teleconference with the FDA highlighted the adverse impact of VVA on women’s lives, including their physical, sexual, and emotional health; clinical experience with the marked efficacy of treatment; and the deleterious effect of the boxed warning on women’s health by discouraging clinician colleagues from prescribing, and women from using, these highly effective low-dose vaginal estrogen products. Specifically, several clinicians reported that many women who have purchased the low-dose vaginal estrogen products, often at significant financial cost, ended up not using them after reading the boxed warning. Comparative blood concentrations of estrogens associated with low-dose vaginal estrogen versus systemic estrogens versus no treatment “Low-dose” vaginal estrogen refers to products such as Estring (vaginal ring releasing estradiol 7. 5 μg/d), Vagifem (10-μg tablets two times a week), and comparable low doses of vaginal creams (eg, Estrace estradiol) or Premarin conjugated estrogens). 17 These products are considered to have a more favorable risk profile than commonly used doses of systemic estrogen therapy because they lead to small, if any, increases in serum estrogen concentrations. 1, 18-23 When low-dose vaginal estrogen is used as directed, reported serum estrogen levels fall generally within the average postmenopausal range (below 20 pg/mL). 1, 18 Reported estradiol levels ranged from 5 to 10 pg/mL with use of the vaginal ring (releasing estradiol approximately 7. 5 μg/d) 19-21 and from 3 to 11 pg/mL with use of the 10-μg vaginal tablet. 22, 23 In contrast, use of 0. 2 mg (200 μg) of estradiol cream led to serum levels of 80 pg/mL. 24 However, a small pilot study showed that using one twentieth of the dose of estradiol cream (a 10-μg dose) was associated with full efficacy in genitourinary tissues, whereas circulating estradiol levels measured using a highly sensitive assay remained within the postmenopausal range of 3 to 10 pg/mL. 22 Conjugated estrogens cream at a dose of 0. 3 mg produced no change in serum estradiol levels, 25 but conjugated estrogens products contain multiple estrogenic compounds, and plasma estradiol levels may not fully reflect estrogenic activity. Among women treated with 0. 3 mg of vaginal conjugated equine estrogens three times a week for 6 months, the serum estrone levels were 61. 6 pg/mL compared with 55. 6 pg/mL at baseline. 25 It is instructive to compare the serum estrogen concentrations of women on low-dose vaginal estrogen with the endogenous estrogen levels in untreated premenopausal and postmenopausal women, as well as with the hormone concentrations of postmenopausal women treated with systemic estrogen. Among untreated women in the Melbourne Women’s Midlife Health Project, the average serum estradiol levels were 78 pg/mL (range, 39-158 pg/mL) 4 years before the final menstrual period, 31 pg/mL (range, 23-42 pg/mL) at the time of the final menstrual period, and 10 pg/mL (range, 8-11 pg/mL) 2 years after menopause. 26 Among postmenopausal women treated with systemic estrogen, serum estrogen concentrations increase markedly. For example, in a 12-week trial of oral estradiol 1 mg/day, the average estradiol level on treatment was 164 pg/mL (range, 86-243 pg/mL), representing a 9. 5-fold increase from baseline menopausal levels. 27 Among women in the Kronos Early Estrogen Prevention Study (average age, 53 y; all within 3 y of their final menstrual period), estradiol levels after treatment with a transdermal patch containing estradiol 50 μg/day were more than three times higher than baseline levels; among women treated with oral conjugated estrogens 0. 45 mg/day, estrone levels were more than twice as high as baseline levels. 28 Thus, treatment with systemic estrogen leads to substantial increases in blood hormone levels compared with baseline, whereas serum hormone levels among women treated with low-dose vaginal estrogen remain within the reference postmenopausal range. Low-dose vaginal estrogen and the endometrium Endometrial tissue response is an extremely sensitive bioassay for estrogenic action and reflects the integration of serum estrogen levels with duration of estrogenic exposure. Three different low-dose vaginal estrogen therapies have been evaluated, and their endometrial effects have been assessed via either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. The largest trial to date is a randomized double-blind controlled study of 1, 612 postmenopausal women in which vaginal estradiol tablets were administered at a dose of 25 μg/day for 2 weeks, followed by a dose of 25 μg two times a week for 12 months. This study demonstrated no increases in serum estradiol levels at 4 and 12 months compared with baseline levels: (mean SD, 15. 7 2. 3 pg/mL baseline vs 15. 5 2. 5 pg/mL 12 mo). 29 Vaginal ultrasound–determined endometrial thickness remained essentially unchanged after 12 months of therapy (mean SD, 3. 1 0. 4 mm baseline vs 2. 9 0. 5 mm 12 mo). 29 There was no change in uterine volume or enlargement of preexisting myomas across 12 months. In a separate study of a vaginal estradiol tablet 10 μg/day, endometrial biopsies were performed in 297 women after 12 months of treatment; 183 women had endometrial tissue that was atrophic or inactive, whereas 111 women had no tissue or had insufficient tissue for diagnosis. There was one case of complex hyperplasia without atypia. 30 Similar findings have been reported in a trial of estradiol vaginal cream given at a dose of 10 μg/day for 3 weeks then 10 μg two times a week. Endometrial thickness remained stable at less than 5 mm during the 12-week treatment. 22 Moreover, in a randomized study of a low-dose vaginal estradiol ring delivering estradiol 7. 5 μg/day, estradiol levels increased less than 1 pg/mL above baseline (P = 0. 59) and endometrial lining thickness at 12 months was similar to baseline, with a mean (SD) change of −0. 14 (0. 53) mm (P = 0. 54). 21 If low-dose vaginal estrogens have either regional or systemic effects beyond their local action, one would expect to observe endometrial proliferation, as determined by either transvaginal ultrasound–measured endometrial thickness or endometrial biopsy. Collectively, these studies demonstrate that low-dose vaginal estrogen therapy, including assessments of three different estradiol preparations at 12 months of evaluation, does not seem to have significant endometrial impact beyond the local vaginal estrogenic effects. Higher dosing, long-term use, and use by women with comorbidities may carry higher risks. Low-dose vaginal estrogen and breast-related outcomes Assessment of the potential biologic effects of low-dose vaginal estrogen on breast tissue can be approached by considering three separate breast breast cancer, and breast Although we could no studies the of breast in to low-dose vaginal a randomized trial a transdermal delivering estradiol μg/day showed no in breast at 2 years compared with breast cancer, a observational study of women, including of vaginal estrogen, indicated no increase in the risk of breast cancer associated with vaginal estrogen Moreover, no increased risk would be based on the results of the estrogen of the years of oral conjugated equine estrogens the were for the and for the no increased risk of breast cancer with conjugated equine estrogens across this time that this to other of estrogen remains However, one would not expect that an even dose of estrogen given and with minimal systemic would have an adverse effect on breast cancer breast this has been reported with doses of vaginal estrogen. However, in a study of low-dose vaginal estrogen only 1 of women of breast pain while the ring was in on the use of 10 μg of low-dose vaginal estrogen no of breast on these collective it is that these products biologic effects on the for women with a history of breast cancer the evidence women with a history of breast cancer The clinical relevance of even small increases in circulating estrogen levels with low-dose vaginal estrogen products in women with breast cancer remains which of estrogen are associated with circulating estradiol levels than 1 Thus, as would be vaginal of low-dose estrogen will lead to serum estradiol levels in women As any above baseline serum estradiol levels may affect the use of any hormone therapy product in women with breast cancer in view of research on the safety of these products in breast cancer In one study, women treatment as or for breast cancer not have higher of with local estrogen use compared with but vaginal estrogen treatment by ring or tablet increase circulating estrogen at least For systemic hormone therapy, results for breast cancer have been found in randomized trials and observational with breast cancer who have symptomatic VVA and do not to nonhormonal therapies are encouraged to the risks and benefits of low-dose vaginal estrogen therapy with their ospemifene has not been tested in women at high risk for breast cancer or with a history of breast no can be given for use in this Low-dose vaginal estrogen and and other outcomes with oral systemic estrogen and as in the and the for the boxed warning, low-dose vaginal estrogen has systemic similar to transdermal estradiol and effects on transdermal estradiol has been shown to have less risk of and the significantly systemic of low-dose vaginal estrogen it even less to increase risk of and other cardiovascular than oral systemic The increased risks of disease, and which have been reported with oral systemic hormone have not been reported with low-dose vaginal estrogen Moreover, long-term of women in the trial of showed no increased risk of or that low-dose vaginal estrogen is unlikely to affect these The 2006 Cochrane review of VVA not evidence of an increased risk of with low-dose but data for women at high risk for these are increase in was observed in the among women years or older who were treated with oral systemic estrogen-progestin therapy results for systemic oral estrogen is no evidence that the minimal of low-dose vaginal estrogen preparations would have the potential to affect risk among women in any group or would have biologic to do of endogenous estrogen concentrations within the reference postmenopausal range The of endogenous estrogen in postmenopausal women is the of via the in and is a risk for breast and endometrial and in the of with these include factors, and in to of is further associated with 2 and higher levels of which also to cardiovascular Thus, observational studies linking endogenous estrogen concentrations within the postmenopausal range to or cancer have potential for by the and are not as a for the use of low-dose vaginal estrogen products. and proposed label changes on these we that the labeling of low-dose vaginal estrogen to include the changes would enhance women’s safety and improve their health and As discussed the boxed warning on these products is based on extrapolations of data from trials of systemic estrogen or estrogen-progestin hormone therapy, which substantially higher levels of exposure. It is that are dramatic differences in estrogen blood levels achieved with low-dose vaginal estrogen therapies compared with systemic estrogen Our view is that the highly boxed warning on low-dose vaginal estrogen is and not evidence-based and is women by discouraging the use of effective that would provide substantial benefits to postmenopausal women with symptomatic We believe that women would be better served by a modified label that more closely reflects the safety profile of low-dose vaginal estrogen and could ultimately enhance safety by emphasizing the key information that women and clinicians need to know about the products. Our as noted is to in the product labeling, in regular text and font, that estrogen and estrogen-progestin given systemically, in higher doses, have been linked to the health conditions currently included in the boxed warning, but that the relevance to low-dose vaginal estrogen remains unknown, given minimal increase in serum estrogen levels with low-dose vaginal estrogen products. We recommend bolding the phrase “report any vaginal bleeding or spotting right away while using ______. ” We also recommend adding in bold “Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product. ” This label change would serve the purpose of informing women of previous research and addressing safety issues while stating that the relevance of past research findings on systemic hormone therapy to the vaginal products is unknown. other statements in the boxed warning, we the would be in regular and font, as of the text would be is the information know about estrogen may increase of cancer of the uterus any vaginal bleeding right away while are using Vaginal bleeding after may be a warning of cancer of the uterus any vaginal bleeding to the higher doses of estrogen is associated with an increased of cancer of the uterus (womb), but the relevance of these findings to low-dose vaginal estrogen is unknown. report any vaginal bleeding or spotting right away while are using Vaginal bleeding after may be a warning of cancer of the uterus any vaginal bleeding or spotting to the not use estrogen to disease, or of this in regular font, not estrogen may increase of or blood higher doses of estrogen may increase of or blood but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen is unknown. estrogen may increase of dementia, based on a study of women years or higher doses of estrogen may increase of dementia, based on a study of women years or but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen is unknown. estrogens with may increase of breast estrogens with may increase of breast cancer, but the relevance of these findings to low-dose vaginal estrogen without is unknown. in Women with a history of cancer of the breast or uterus (womb), or other hormone-sensitive cancers, are encouraged to consult their oncologist before using this product. the in regular and about need treatment with We believe that these label modifications will improve women’s 1 for the Working Group on Women’s Health and Well-Being in Menopause of and report no is a and has for on and is a and has for on and on for is on the for and is a to the of for and has served as a to are or past members of the of