Scientific Workshop on Labeling “Lower” Dose Estrogen-Alone Products for Symptoms of Vulvar and Vaginal Atrophy (VVA)

FDA Workshop—November 10, 2015

FDA is announcing a public workshop and an opportunity for public comment on the topic of the labeling for lower-dose estrogen products delivered vaginally, intended to treat moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. The workshop will address whether the current “Boxed Warnings” section in the labeling is applicable in whole or in part to these lower-dose estrogen products. This meeting, a scientific workshop, will provide the opportunity for FDA to seek input from experts on the Boxed Warnings section and estrogen exposure data relative to labeling of these lower-dose estrogen-alone products.

Detailed information about this workshop is provided here. The meeting will be held at the FDA White Oak Campus, 10903 New Hampshire Avenue, Building 31, Conference Center, Section A of the Great Room (Room 1503), Silver Spring, Maryland, 20993. Entrance for the public meeting participants (non-FDA employees) is through Building 1.

Public Comment: For those who wish to give public comment during the November 10, 2015, public meeting, please email FDA by October 16, 2015, to register for this session. Additional registration will occur at the registration desk on the day of the meeting on a first-come, first-served basis if there is still time available during this session. Seating will be limited, so early registration is recommended.

Electronic Comments: Send your comments electronically by going here and look for the “Comment Now!” button on the upper right (must be received by October 16, 2015, and you must identify your comments with the Agency/Docket Number FDA-2015-N-3275). Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Maryland, 20852.

Citizens’ Petition

NAMS has published a commentary in the September 2014 issue of Menopause to encourage modifications to the product labeling of low-dose vaginal estrogen (Manson JE, Goldstein SR, Kagan R, et al. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause. 2014;21:911-916). If you would like to indicate your support for this proposal, please sign the Citizens’ Petition here.

Overview of the Proposal for a Label Change and Removal of Boxed Warning for Low-Dose Vaginal Estrogen

In the commentary published in the September 2014 issue of Menopause, several clinicians and researchers summarize the rationale for modifications to the product 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 spearheaded an effort to encourage consideration of alternative labeling that enhances patient safety by highlighting relevant cautions without an alarming Boxed Warning. The authors of the report (Drs. JoAnn Manson, Steven Goldstein, Risa Kagan, Andrew Kaunitz, James Liu, JoAnn Pinkerton, Robert Rebar, Peter Schnatz, Jan Shifren, Cynthia Stuenkel, Margery Gass, and Wulf Utian) represent the Working Group on Women’s Health and Well-Being in Menopause and have affiliations with a number of medical societies, including The North American Menopause Society (NAMS), 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. All of the authors are current or former members of the NAMS Board of Trustees, and this effort addresses a key concern of NAMS membership.

The commentary in Menopause provides the rationale and justification for product labeling modifications for low-dose vaginal estrogen. The article highlights the following points: vulvovaginal atrophy (also known as genitourinary syndrome of menopause) is a common and progressive condition that adversely affects the health and quality of life of postmenopausal women; the Boxed Warning (about risks of endometrial and breast cancer, cardiovascular disease, and probable dementia) reflects estrogen class labeling and is based on extrapolations of data from clinical trials of systemic hormone therapy that involve substantially higher levels of exposure; the Boxed Warning is unjustified based on available evidence; and the Boxed Warning discourages clinicians from prescribing the product and patients from taking it even after purchase. The commentary highlights the dramatic differences in blood levels of hormones achieved by low-dose vaginal estrogen versus conventional systemic estrogen therapy, as well as the 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.

The authors propose 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 have about the products. The proposal is to state in the product labeling and inserts, 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. The authors recommend bolding the cautions that women report any vaginal bleeding or spotting right away while using (the product). They 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 oncologists before using this product.” The authors propose that these label changes would improve patient safety because the relevant information and cautions would 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 the previous research, addressing safety issues, while stating that the relevance of past research findings on systemic hormone therapy to low-dose vaginal estrogen is unknown.

Again, if you are interested in signing on to this proposal and the Citizens’ Petition, please provide your name, title, affiliations, and email here.