FDA Scientific Workshop – Labeling of Low-Dose Vaginal Estrogen Products

November 13, 2015

My name is Cindy Pearson, and I am the Executive Director of The National Women’s Health Network. The National Women’s Health Network is a nonprofit advocacy organization that works to improve the health of all women. We are supported by our members and do not accept financial support from drug companies or medical device manufacturers. We bring the voices, concerns and needs of women consumers to policy and regulatory tables.

Since the Network’s founding 40 years ago, we have brought the voices of women to the FDA, advocating for medical products that meet women’s real life needs and a drug development process that reflects women's lived experiences.

We appreciate the FDA’s examination of this important topic. The question of whether vaginal estrogen products increase the risk of stroke, pulmonary embolism, deep venous thrombosis, and myocardial infarction is important. Low-dose vaginal estrogen products probably don’t increase risk, and we support a label change in this regard. However, it is important to be clear to consumers about what we do and do not know. We have three major concerns, and as such, we respectfully submit the following for consideration by the FDA.

1. Doses of vaginal estrogens vary; please be clear about what low-dose means.

Low doses of vaginal estrogen are effective in treating sexual discomfort, but different estrogens are available and different doses are described as “low” or “ultra-low” doses. The FDA has defined lower-dose as products with less than 0.625 mg of conjugated estrogens or less than 0.0375 mg estradiol. However, studies show that daily doses of conjugated estrogens 0.3 mg (300 mcg), estradiol 10 mcg (0.01 mg), and estriol 30 mcg (0.03 mg) are effective doses; why include higher doses at all? Clinicians may recommend different doses, some of which are not low. For example, the labeled range of doses on vaginal conjugated estrogens ranges from 0.3 mg to 1.25 mg (.625 mg/ ml; daily dose 0.5-2.0 ml x 21/30 days. (Premarin label). The higher dose has been linked to higher blood concentrations and more vaginal bleeding and other adverse effects than lower doses (Spurling).

2. Evidence is needed regarding the relationship between unopposed vaginal estrogen cream use and increased risk of endometrial hyperplasia and endometrial.

In our experience, women are often told by clinicians that progestins are unnecessary with vaginal estrogens. While the labels of vaginal estrogen preparations state that progestins reduce endometrial cancer rates in users of estrogen, it is unclear whether progestins are being recommended. Progestins have their own health risks, which need to be taken into account if they are being prescribed with vaginal estrogens. We understand that many clinicians avoid progestins and instead monitor endometrial thickness with vaginal ultrasound. That is a reasonable practice but whether it is even necessary begs for further research.

While vaginal estrogens have a small effect on increased blood concentrations compared to oral estrogens, that alone is not proof of safety regarding the endometrium, especially given the proximity of the uterus to  the vagina and the fact that the cervix of the uterus is directly  exposed to estrogen from creams, tablets, or rings. Different formulations and doses may have different effects.  In fact, a study comparing conjugated estrogen cream 1.25 mg to a 17-beta estradiol tablet (25 micrograms) found that the conjugated estrogen cream caused a 7-fold increase in endometrial proliferation (14% vs. 2%) , compared to an estrogen  tablet (Rioux 2000); another study found that conjugated estrogen cream caused twice as much endometrial proliferation (13% vs. 6%) as  an estrogen ring (presumably) (Nachtigall 1995). While most studies have shown no effect of vaginal estrogens on endometrial hyperplasia, we were unable to identify studies that were longer than 12 months long. An unknown level of risk is not synonymous with safety. Women with vulvovaginal symptoms may be using estrogen for years or decades; long-term risks need to be elucidated.

3. Non-hormonal preparations should be first line treatment.

Randomized controlled trials show that regular use of vaginal moisturizer, is as effective as vaginal estrogen in treating vulvovaginal symptoms. (Sinha 2013) Genistein-based creams are also helpful as are hyaluronic acid-containing creams - although these are less effective than estrogen or genistein. (Sinha 2013) Women can also be informed that regular sexual activity helps symptoms.

We would also urge the FDA to consider only patient comfort, not levels of estrogenization of vaginal cells, as the best endpoint for studies. Some preparations help symptoms, but do not change the appearance of vaginal cells. We would argue that patient comfort is the goal, not the cosmetic appearance of cells inside the vagina.

Low-dose vaginal estrogen products carry a lower risk of adverse events than oral estrogens, and we support a label change that distinguishes between different routes of administration and doses. However, all doses and preparations are not equal. What constitutes a low-dose product should be specified, and warnings should be clear regarding the lack of data on long-term use and endometrial hyperplasia. And clinicians should emphasize that non-hormonal preparations can be just as effective as hormonal preparations.

Cindy Pearson was the NWHN’s Executive Director from 1996 to 2021. One of the nation's leading advocates for women's health, Cindy often testified before Congress,  NIH and the FDA and was frequently featured in the news as a consumer expert on women’s health issues. When she retired, Cindy received a Congressional Resolution in honor of her outstanding contributions to the health of women and girls.

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References

  1. Non-hormonal topical treatment of vulvovaginal atrophy: an up-to-date overview. Sinha A, Ewies AA. Climacteric. 2013 Jun;16(3):305-12. doi: 10.3109/13697137.2012.756466.
  2. Maturitas. 1995 Dec;22 Suppl:S43-7. Clinical trial of the estradiol vaginal ring in the U.S. Nachtigall LE1.
  3. Menopause. 2000 May-Jun;7(3):156-61. 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Rioux JE1, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS.
  4. J Obstet Gynaecol. 2015 Nov;35(8):783-7. doi: 10.3109/01443615.2015.1011104. Epub 2015 Feb 24. Topical administration of isoflavones for treatment of vaginal symptoms in postmenopausal women: A systematic review of randomised controlled trials. Ghazanfarpour M1, Latifnejad Roudsari R2, Treglia G3, Sadeghi R4.
  5. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, Olivera CK, Abed H, Balk EM, Murphy M; Society of Gynecologic Surgeons Systematic Review Group. Obstet Gynecol. 2014 Dec;124(6):1147-56
  6. Suckling JA, Kennedy R, Lethaby A, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD001500. DOI: 10.1002/14651858.CD001500.pub2.
  7. Premarin label http://labeling.pfizer.com/showlabeling.aspx?id=132