Document ID: FDA-2015-N-3275-0001
Agency: fda
Document Type: Notice
Title: Labeling Lower-Dose Estrogen-Alone Products for Symptoms of 
Vulvar and Vaginal Atrophy
Posted Date: 2015-09-28T04:00Z

[Federal Register Volume 80, Number 187 (Monday, September 28, 2015)]
[Notices]
[Pages 58258-58259]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-24509]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-3275]

Labeling Lower-Dose Estrogen-Alone Products for Symptoms of 
Vulvar and Vaginal Atrophy

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
meeting 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 
(VVA) due to menopause. Lower-dose estrogen products means products 
that contain less than the 0.625 milligrams (mg) of conjugated 
estrogens used in the Women's Health Initiative Study, and estradiol 
products containing 0.0375 mg and below. Lower-dose estrogen products 
are now approved for the treatment of moderate to severe symptoms of 
VVA due to menopause, and some in the scientific/medical community have 
questioned 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 an 
opportunity for FDA to seek input from experts on the Boxed Warnings 
section, estrogen exposure data, and pharmacokinetic (PK)/
pharmacodynamic (PD) relationships relative to labeling lower-dose 
estrogen-alone products intended to treat moderate to severe symptoms 
of VVA due to menopause.

DATES: The public meeting will be held on November 10, 2015, from 8:30 
a.m. to 5 p.m. Registration to attend the meeting must be received by 
October 16, 2015, with onsite registration available between 7 a.m. and 
8 a.m. the day of the meeting. See the SUPPLEMENTARY INFORMATION 
section for information on how to register for this meeting. Submit 
either electronic or written comments by October 16, 2015.

ADDRESSES: The meeting will be held at the FDA White Oak Campus, 10903 
New Hampshire Ave., Bldg. 31 Conference Center, Section A of the Great 
Room (Rm. 1503), Silver Spring, MD 20993. Entrance for the public 
meeting participants (non-FDA employees) is through Building 1, where 
routine security check procedures will be performed. For more 
information on parking and security procedures, please refer to http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.
    Submit electronic comments to www.regulations.gov. Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All 
comments should be identified with the docket number found in brackets 
in the heading of this document.
    FDA will post the agenda approximately 5 days before the meeting at 
http://www.fda.gov/Drugs/NewsEvents/ucm459690.htm.

FOR FURTHER INFORMATION CONTACT: Kimberly Shiley, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 22, Rm. 5377, Silver Spring, MD 20993, 301-796-
2117, email: Kimberly.Shiley@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Introduction

    The loss of ovarian function with menopause leads to a drastic 
reduction in circulating estrogen concentration, which in turn leads to 
physiologic changes to the vulva, vagina, and lower urinary tract. 
Reduced circulating estrogen concentration results in an increase in 
vaginal pH, a thinning and reduction of the folds of the vaginal 
lining, reduction of vaginal secretions, and loss of elasticity in 
vaginal tissues. Symptoms of decreased circulating estrogen include 
vaginal and vulvar itching and/or irritation, vaginal dryness and 
vaginal pain (dyspareunia), and/or bleeding with intercourse. Not all

[[Page 58259]]

postmenopausal women have symptoms of VVA that require treatment, but 
some women (particularly those 5 to10 years postmenopausal), when 
asked, will report one or more of the above symptoms, which they deem 
to be bothersome and self-categorize as moderate to severe in 
intensity. To date, the Agency has approved estrogen products (both 
estrogen-alone and estrogen plus progestin) for the indications of 
``treatment of moderate to severe vaginal dryness, a symptom of vulvar 
and vaginal atrophy due to menopause'' and ``treatment of moderate to 
severe dyspareunia, a symptom of vulvar and vaginal atrophy due to 
menopause.''
    Estrogen-alone products have Boxed Warnings stating:
    (1) There is an increased risk of endometrial cancer in a woman 
with a uterus who uses unopposed estrogen;
    (2) estrogen-alone therapy should not be used for the prevention of 
cardiovascular disease or dementia;
    (3) an increased risk of stroke and deep vein thrombosis was 
reported in the Women's Health Initiative (WHI) estrogen-alone 
substudy; and
    (4) an increased risk of probable dementia in postmenopausal women 
65 years of age and older was reported in WHI Memory Study (WHIMS) 
estrogen-alone ancillary study.
    The WHI estrogen-alone studies evaluated only a single estrogen 
dose consisting of 0.625 mg of conjugated estrogen. As lower-dose 
estrogen products are now approved for the treatment of moderate to 
severe symptoms of VVA due to menopause, some in the scientific/medical 
community have questioned whether these statements in the Boxed Warning 
section are applicable in whole or in part to the lower-dose estrogen 
products.

II. Discussion Topics

    The scientific workshop on November 10th will include discussions 
of scientific challenges related to the following topics:
     The relevance to lower-dose estrogen products of the Boxed 
Warnings related to the WHI findings that: (1) Estrogens should not be 
used for the prevention of cardiovascular disease or dementia, (2) 
there is an increased risk of stroke and deep vein thrombosis in women 
treated with estrogen-alone, and (3) there is an increased risk of 
probable dementia in postmenopausal women 65 years of age and older 
treated with estrogen-alone.
     How to educate prescribers on the interpretation of 
estrogen exposure data across various estrogen dosage forms indicated 
for treatment of moderate to severe symptoms of vulvar and vaginal 
atrophy due to menopause. Presentation of basic PK and clinical 
pharmacology data concepts and an informed framework for comparing 
various estrogen products for prescribing purposes.
     Discuss the level of available data supporting that a 
given estrogen serum concentration is or is not related to adverse 
outcomes (for example, pulmonary emboli, deep venous thrombosis, and 
myocardial infarction).
     Presentation and discussion of PD biomarkers for 
thrombosis. Presentation of a comparison of metabolic profiles from 
various products, key clotting factors responsible for thrombosis, and 
PK/PD relationships.

III. Meeting Attendance and Participation

    If you wish to attend this meeting, email 
FDAVVAworkshop@fda.hhs.gov. Please register by October 16, 2015. Those 
who are unable to attend the meeting in person can register to view a 
live Webcast of the meeting. You will be asked to indicate in your 
registration whether you plan to attend in person or via the Webcast. 
Your registration should also contain your complete contact 
information, including name, title, affiliation, address, email 
address, and telephone number.
    Seating will be limited, so early registration is recommended. 
Registration is free and will be on a first-come, first-served basis. 
However, FDA may limit the number of participants from each 
organization based on space limitations. Registrants will receive 
confirmation once they have been accepted. Onsite registration on the 
day of the meeting will be based on space availability. If you need 
special accommodations because of disability, please contact Kimberly 
Shiley (see FOR FURTHER INFORMATION CONTACT) at least 7 days before the 
meeting.
    FDA will hold an open public comment session during the November 
10th public meeting to give the public an opportunity to comment. 
Register for this session at FDAVVAworkshop@fda.hhs.gov by October 16, 
2015. 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.
    Docket Comments: Regardless of attendance at the meeting, you can 
submit electronic or written comments, including responses to the 
public docket (see ADDRESSES), by October 16, 2015. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.
    Transcripts: Transcripts for the November 10th meeting will be 
posted, when available, at http://www.fda.gov/Drugs/NewsEvents/ucm401167.htm.

    Dated: September 22, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-24509 Filed 9-25-15; 8:45 am]
BILLING CODE 4164-01-P