Product Labeling for Low-dose Vaginal Estrogen
Product Labeling for Low-dose Vaginal Estrogen
Based on these data, we submit that revisiting the labeling of low-dose vaginal estrogen to include the changes below would enhance women's safety and improve their health and well-being. As discussed previously, the boxed warning on these products is based on extrapolations of data from trials of systemic estrogen or combination estrogen-progestin hormone therapy, which involve substantially higher levels of exposure. It is noteworthy that there are dramatic differences in estrogen blood levels achieved with low-dose vaginal estrogen therapies compared with systemic estrogen administration. Our view is that the highly visible boxed warning on low-dose vaginal estrogen is unsubstantiated and not evidence-based and is harming women by discouraging the use of effective treatments that would provide substantial benefits to postmenopausal women with symptomatic VVA. 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 proposal, as noted above, is to mention in the product labeling, in regular text and font, that estrogen and estrogenprogestin 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 current vaginal products is unknown.
Regarding other statements in the boxed warning, we propose the following (all would be listed in regular and unbolded font, except as noted; none of the text would be boxed):
What is the most important information I should know about _____?
* Instead of: Using estrogen alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find the cause.
Change to: Using higher doses of estrogen alone is associated with an increased chance of getting cancer of the uterus (womb), but the relevance of these findings to low-dose vaginal estrogen is unknown. Nonetheless, report any vaginal bleeding or spotting right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any vaginal bleeding or spotting to find the cause.
* Include: Do not use estrogen alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).
Comment: Include this in regular unbolded font, not boxed.
* Instead of: Using estrogen alone may increase your chances of getting strokes or blood clots.
Change to: Using higher doses of estrogen may increase your chances of getting strokes or blood clots, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown.
* Instead of: Using estrogen alone may increase your chance of getting dementia, based on a study of women aged 65 years or older.
Change to: Using higher doses of estrogen may increase your chance of getting dementia, based on a study of women aged 65 years or older, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown.
* Instead of: Using estrogens with progestins may increase your chance of getting breast cancer.
Change to: Using estrogens with progestins may increase your chance of getting breast cancer, but the relevance of these findings to low-dose vaginal estrogen without progestins is unknown.
Add 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.
Include the statement below in regular unbolded font:
* You and your healthcare provider should talk regularly about whether you still need treatment with _______.
We believe that these label modifications will improve women’s health.
Conclusions and Proposed Label Changes
Based on these data, we submit that revisiting the labeling of low-dose vaginal estrogen to include the changes below would enhance women's safety and improve their health and well-being. As discussed previously, the boxed warning on these products is based on extrapolations of data from trials of systemic estrogen or combination estrogen-progestin hormone therapy, which involve substantially higher levels of exposure. It is noteworthy that there are dramatic differences in estrogen blood levels achieved with low-dose vaginal estrogen therapies compared with systemic estrogen administration. Our view is that the highly visible boxed warning on low-dose vaginal estrogen is unsubstantiated and not evidence-based and is harming women by discouraging the use of effective treatments that would provide substantial benefits to postmenopausal women with symptomatic VVA. 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 proposal, as noted above, is to mention in the product labeling, in regular text and font, that estrogen and estrogenprogestin 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 current vaginal products is unknown.
Regarding other statements in the boxed warning, we propose the following (all would be listed in regular and unbolded font, except as noted; none of the text would be boxed):
What is the most important information I should know about _____?
* Instead of: Using estrogen alone may increase your chance of getting cancer of the uterus (womb). Report any unusual vaginal bleeding right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find the cause.
Change to: Using higher doses of estrogen alone is associated with an increased chance of getting cancer of the uterus (womb), but the relevance of these findings to low-dose vaginal estrogen is unknown. Nonetheless, report any vaginal bleeding or spotting right away while you are using ______. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any vaginal bleeding or spotting to find the cause.
* Include: Do not use estrogen alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).
Comment: Include this in regular unbolded font, not boxed.
* Instead of: Using estrogen alone may increase your chances of getting strokes or blood clots.
Change to: Using higher doses of estrogen may increase your chances of getting strokes or blood clots, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown.
* Instead of: Using estrogen alone may increase your chance of getting dementia, based on a study of women aged 65 years or older.
Change to: Using higher doses of estrogen may increase your chance of getting dementia, based on a study of women aged 65 years or older, but the relevance of these findings to low-dose vaginal estrogen, which leads to minimal increase in blood estrogen levels, is unknown.
* Instead of: Using estrogens with progestins may increase your chance of getting breast cancer.
Change to: Using estrogens with progestins may increase your chance of getting breast cancer, but the relevance of these findings to low-dose vaginal estrogen without progestins is unknown.
Add 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.
Include the statement below in regular unbolded font:
* You and your healthcare provider should talk regularly about whether you still need treatment with _______.
We believe that these label modifications will improve women’s health.