Product Labeling for Low-dose Vaginal Estrogen
Product Labeling for Low-dose Vaginal Estrogen
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. 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). 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.
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. 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). 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.