NAMS Leaders Request Labeling Change for Low-dose Vaginal Estrogen for Vulvovaginal Atrophy

November 2015 -- Arising from concerns raised during the Town Hall at the 2013 Annual Meeting of The North American Menopause Society (NAMS), Dr. JoAnn Manson spearheaded a Working Group that determined that current labeling for low-dose vaginal estrogen used for vulvovaginal atrophy (VVA) indications was not evidence based, overstated risks through extrapolation of findings from trials of oral systemic hormone therapy, and did not accurately reflect the safety profile of low-dose vaginal estrogen. Under her leadership, the Working Group encouraged FDA to modify the product labeling of low-dose vaginal estrogen and published its position in the September 2014 issue of Menopause.

On November 10, 2015, FDA convened a workshop on use of lower-dose vaginal estrogen used to treat VVA. Serving on the scientific panel were two NAMS leaders: Executive Director Dr. JoAnn Pinkerton and Executive Director Emeritus, Dr. Margery Gass.

During the meeting, Dr. Pinkerton presented the suggestions from the Working Group:

  1. That low-dose vaginal estrogen products approved for VVA have very different risks compared with those reported in the Boxed Warning
  2. That low-dose vaginal estrogen products deserve a different label
  3. That the label should accurately reflect relevant evidence-based information
  4. That the label should highlight the following safety information:
    1. Vaginal bleeding or spotting should be reported promptly, because it may be a sign of endometrial cancer
    2. Women with estrogen-sensitive cancers should consult with their oncologists before using low-dose vaginal estrogen products

The available evidence about lower-dose vaginal estrogen:

  1. Significantly lower doses than systemic doses
  2. Vaginal products are transdermal and thus avoid first-pass hepatic metabolism
  3. Pharmacokinetic data show only small or minimal changes in systemic blood levels, staying within the postmenopausal range of less than 20 pg estradiol
  4. Different end-organ response, including lack of endometrial or breast stimulation in year-long randomized, controlled trial (RCT)
  5. Lack of hemostatic changes with low-dose transdermal compared with oral (ACOG Committee Bulletin 556. Obstet Gyncecol. 2013;121[4]:887-890)
  6. Lack of RCT or observational data linking these products to cancer, heart disease, dementia, or thrombosis
  7. The Women’s Health Initiative (WHI) systemic estrogen-progestin therapy data have unknown relevance for these products, given the minimal increase in systemic estradiol and estrone levels
  8. Women deserve to have a label that reflects accurate and relevant evidence-based information
  9. Recommend highlighting (bolding) on the label to instruct women to report vaginal bleeding and that women with estrogen-sensitive cancers consult their oncologists before use
  10. On the basis of current data, the low-dose vaginal therapies approved for VVA have very different risks than those reported in the Boxed Warning

NAMS’ efforts to change the product label have been supported by the Endocrine Society, the American Congress of Obstetricians and Gynecologists, the American Medical Women’s Association, the American Society for Reproductive Medicine, the Academy of Women’s Health, the Society for Women’s Health Research, Nurse Practitioners in Women’s Health, the American Association of Nurse Practitioners, and the Society for Women’s Health Research, among others. The Citizen’s Petition launched by NAMS received 430 signatures submitted to FDA and currently has 625 signatures.

Dr. Pinkerton has provided key points of the testimony of prominent NAMS leaders, among others, who spoke at the Public Comment Session of the FDA workshop in support of label change:

Dr. Steve Goldstein, Professor at New York University, presented pharmacokinetic data showing that low-dose vaginal estrogen does not raise serum levels higher than the normal menopause range.

Dr. Risa Kagan, Chair of the Scientific Program Committee for the 2013 NAMS Annual Meeting, with a Pre-Meeting Symposium on VVA, presented the adverse effects of VVA on self-esteem, quality of life, recurrent urinary tract infections, vaginitis, and painful sex and exacerbation of patient’s fear and anxiety from reading the label.

Dr. Lisa Larkin, Director of the University of Cincinnati Women’s Health Center, testified to the lack of data that show that low-dose vaginal therapy has the same risks as systemic estrogen. In the absence of data showing similar risks, mandating the same class label is not justified. Harm comes to women from the package insert because of lack of use over fear of unsubstantiated risks or going to non-FDA-approved compounded therapy in the mistaken belief that it is safer because there are no package inserts.

Dr. Sharon Parish, President of the International Society for the Study of Women’s Sexual Health (ISSWSH), presented data from six surveys showing the negative effect of VVA on sexual health and a recent focus group on how negative sexual function affected interpersonal relationships, self-esteem, and quality of life. ISSWSH supports accurate labeling for access to care.

Dr. Cynthia Stuenkel, Chair of the recent Endocrine Society Treatment of Symptoms of the Menopause clinical guidelines, testified that oral systemic higher-dose estrogen is linked to the risks shown in the WHI but is of unknown relevance to the lower-dose products. If the only concern is VVA, first-line treatment is local vaginal therapy. For women with cancer, choice of therapy should be a shared decision with their oncologists. Available evidence does not support Boxed Warnings on lower-dose vaginal estrogen because of increased risk of heart disease, stroke, blood clot, dementia, or cancer.

Dr. Carolyn Wilson, Assistant Professor of Obstetrics and Gynecology at the University of Virginia, practices in an academic setting and in the community and finds that in both places, patients don’t fill the prescription or read the label and then don’t take it because they are frightened by the risks outlined in the label.

Dr. Wen Shen directs Johns Hopkins Menopause Clinic for cancer survivors and prescribes low-dose estrogen after discussion and counseling of patient and with oncologist approval to treat VVA and improve quality of life.

Dr. James Simon, Clinical Professor at George Washington University, testified that the WHI findings 13 years ago changed the world but that FDA added Boxed Warnings to all estrogen products without any information that the findings were relevant to lower-dose vaginal products.

Dr. Sebastian Mirkin, Chief Medical Officer at TherapeuticsMD, presented differences in pharmacokinetic data, decreased hepatic exposure, and lack of end-organ response with documented endometrial safety at 1 year compared with oral therapy that has 8% hyperplasia at 1 year and recommended accurate and relevant information in the label.

Ms. Jan Erickson, National Organization for Women, testified that the patient label is misleading and terrifying, that the label has discouraged women from using the therapy, and that providers supported the Working Group’s request to have the label changed.

Ms. Gay Johnson, Chief Executive Officer of Nurse Practitioners in Women’s Health, testified that the Boxed Warning overstates potential risks and discourages providers from prescribing vaginal estrogen for VVA.

Ms. Cindy Pearson, Executive Director of the National Women’s Health Network, testified that women’s health improved by label changes instigated by the WHI. Labels should provide useful information to providers and consumers, and labels should be able to provide specific information about the risks of low-dose vaginal products.

NAMS members will be kept apprised of FDA review of this request to change the Boxed Warning.


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