Estriol: Summary Report

Item Type Report

Authors Yoon, SeJeong; Gianturco, Stephanie L.; Pavlech, Laura L.; Storm, Kathena D.; Yuen, Melissa V.; Mattingly, Ashlee N.

Publication Date 2020-02

Keywords Estriol; Compounding; Food, Drug, and Cosmetic Act, Section 503B; Food and Drug Administration; Outsourcing facility; Drug compounding; Legislation, Drug; United States Food and Drug Administration

Rights Attribution-NoDerivatives 4.0 International

Download date 30/09/2021 11:06:59

Item License http://creativecommons.org/licenses/by-nd/4.0/

Link to Item http://hdl.handle.net/10713/12108 Summary Report

Estriol

Prepared for: Food and Drug Administration Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List Grant number: 2U01FD005946

Prepared by: University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) University of Maryland School of Pharmacy

February 2020

This report was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (U01FD005946) totaling $2,342,364, with 100 percent funded by the FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by, the FDA/HHS or the U.S. Government.

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Table of Contents

REVIEW OF NOMINATION ...... 4 METHODOLOGY ...... 4 Background information...... 4 Systematic literature review ...... 4 Outreach to medical specialists and specialty organizations ...... 7 Survey ...... 7 CURRENT AND HISTORIC USE...... 8 Summary of background information ...... 8 Summary of literature review ...... 10 Summary of focus groups/interviews of medical experts and specialty organizations ...... 21 Summary of survey results...... 23 CONCLUSION ...... 29 APPENDICES ...... 30 Appendix 1. References...... 30 Appendix 2. Survey instrument ...... 51

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Table of Tables

Table 1. Participating associations ...... 8 Table 2. Associations that declined participation...... 8 Table 3. Currently approved products – US...... 9 Table 4. Currently approved products – select non-US countries and regions ...... 9 Table 5. Types of studies ...... 10 Table 6. Number of studies by country ...... 10 Table 7. Number of studies by combinations ...... 12 Table 8. Dosage by indication – US ...... 13 Table 9. Dosage by indication – non-US countries ...... 15 Table 10. Compounded products – US ...... 19 Table 11. Compounded products – non-US countries ...... 20 Table 12. Overview of interviewees ...... 21 Table 13. Characteristics of survey respondents ...... 23 Table 14. Types of products used, prescribed, or recommended ...... 23 Table 15. Compounded use of estriol in practice ...... 25 Table 16. Indications for which estriol is considered a standard therapy ...... 27 Table 17. Reasons for using compounded product instead of the FDA-approved products ...... 28 Table 18. Change in frequency of compounded estriol usage over the past 5 years ...... 28 Table 19. Do you stock non-patient specific compounded estriol in your practice? ...... 29 Table 20. Questions related to stocking non-patient specific compounded estriol ...... 29

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REVIEW OF NOMINATION Estriol (UNII code: FB33469R8E) was nominated for inclusion on the 503B Bulks List by Fagron for use in vaginal atrophy via a 0.005-0.1% vaginal cream and gel. Reasons provided for nomination to the 503B Bulks List include: • There are no FDA-approved products. • Estriol has the advantage of being highly effective at ultra-low dosing which can be extremely important for breast cancer survivors where estrogen replacement is riskier. Even at estradiol's lowest dose, estriol is still less stimulatory on other tissues in the body. • Estriol is approximately 1000 times weaker than estradiol, making it a clear choice over estradiol or conjugated estrogen.

METHODOLOGY Background information The national medicine registers of 13 countries and regions were searched to establish the availability of estriol products in the United States (US) and around the world. The World Health Organization, the European Medicines Agency (EMA), and globalEDGE were used to identify regulatory agencies in non- US countries. The medicine registers of non-US regulatory agencies were selected for inclusion if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information, specifically, product trade name, active ingredient, strength, form, route of administration (ROA), and approval status, provided in a useable format. Based on these criteria, the medicine registers of 13 countries/regions were searched: US, Canada, European Union (EU), United Kingdom (UK), Ireland, Belgium, Latvia, Australia, New Zealand, Saudi Arabia, Abu Dhabi, Hong Kong, and Namibia. Both the EMA and the national registers of select EU countries (Ireland, UK, Belgium, and Latvia) were searched because some medicines were authorized for use in the EU and not available in a member country and vice versa. Each medicine register was searched for estriol; name variations of estriol were entered if the initial search retrieved no results. The following information from the search results of each register was recorded in a spreadsheet: product trade name; active ingredient; strength; form; ROA; status and/or schedule; approval date. Information was recorded only for products with strengths, forms, and/or ROA similar to those requested in the nominations. In addition to the aforementioned medicine registers, the DrugBank database (version 5.1.4) and the Natural Medicines database were searched for availability of over-the-counter (OTC) products containing estriol. The availability of OTC products (yes/no) in the US and the ROA of these products were recorded in a spreadsheet. Individual product information was not recorded.

Systematic literature review Search strategy Two databases (PubMed and Embase) were searched including any date through December 28, 2018. The search included a combination of (epiestriol[TIAB] OR ovestin[TIAB] OR estriol[TIAB] OR oestriol[TIAB]) AND (clinical[TIAB] OR therapy[TIAB] OR treatment[TIAB] OR therapeutic*[TIAB] OR vaginal[TIAB] OR vaginitis[TIAB] OR atrophy[TIAB] OR atrophic[TIAB])

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NOT autism AND (humans[MeSH Terms] AND English[lang]). Peer-reviewed articles as well as grey literature were included in the search. Search results from each database were exported to Covidence®, merged, and sorted for removal of duplicate citations. Study selection Articles were not excluded on the basis of study design. Articles were considered relevant based on the identification of a clinical use of estriol or the implementation of estriol in clinical practice. Articles were excluded if not in English, a clinical use was not identified, incorrect salt form, or if the study was not conducted in humans. Screening of all titles, abstracts, and full-text were conducted independently by two reviewers. All screening disagreements were reconciled by a third reviewer. Data extraction A standard data extraction form was used to collect study authors; article title; year published; journal title; country; indication for estriol use; dose; strength; dosage form; ROA; frequency and duration of therapy; any combination therapy utilized; if applicable, formulation of compounded products; study design; and any discussion surrounding the use of estriol compared to alternative therapies. Results Please refer to Figure 1.

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Figure 1. Summary of literature screening and selection (PRISMA 2009 Flow Diagram)

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Outreach to medical specialists and specialty organizations Using the indication from the nomination and the results of the literature review, eight (8) medical specialties that would potentially use estriol were identified: dermatology, endocrinology, naturopathy, neurology, obstetrics and gynecology, primary care, rheumatology, and urology. Semi-structured interviews were conducted with subject matter experts within these specialties. Interviews lasted from 30-75 minutes and were conducted either via telephone or in-person. Criteria for selecting subject matter experts included recommendations provided by specialty professional associations, convenient geographic location, authorship within the specialty, or referral by an interviewee. Up to nine (9) interviews were conducted per substance. Five (5) experts were contacted for interviews, of which four (4) accepted. One (1) medical expert specializing in neurology failed to respond to the interview request. Most interviews were recorded and transcribed via ©Rev.com; one (1) interview was not recorded due to equipment failure. QSR International’s NVivo 12 software was utilized for qualitative data analysis. The University of Maryland, Baltimore IRB and the Food & Drug Administration RIHSC reviewed the study and found it to be exempt. Subject matter experts provided their oral informed consent to participate in interviews.

Survey General professional medical associations and specialty associations for dermatology, endocrinology, naturopathy, neurology, obstetrics and gynecology, primary care, rheumatology, and urology, identified from the nomination, literature review, and interviews, were contacted to facilitate distribution of an online survey. A Google™ search was conducted to identify relevant professional associations within each specialty. Associations were included if their members are predominantly practitioners, national associations, and organizations focused on practice within the US. Organizations without practicing physicians and state or regional organizations were excluded. The association’s website was searched in order to identify the email of the executive director, regulatory director, media director, association president, board members, or other key leaders within the organization to discuss survey participation. If no contact information was available, the “contact us” tab on the association website was used. An online survey was created using Qualtrics® software (Provo, UT). The survey link was distributed to thirteen (13) associations. If an association had more than one (1) substance with indications relevant to that specialty, substances were combined into one (1) survey with no more than 14 substances per survey. Table 1 highlights the associations that agreed to distribute the survey link and Table 2 includes the associations that declined to participate. Additionally, single substance surveys were created and posted on the project website which was shared with survey participants. Participation was anonymous and voluntary. The estimated time for completion was 30 minutes with a target of 50 responses per survey. The Office of Management and Budget (OMB) approved this project.

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Table 1. Participating associations

Specialty Association

American Academy of Dermatology (AAD) Dermatology American Society for Dermatologic Surgery (ASDS)

Naturopathy American Association of Naturopathic Physicians (AANP)

Primary Care American Academy of Environmental Medicine (AAEM)

Rheumatology American College of Rheumatology (ACR)

Table 2. Associations that declined participation

Specialty Association Reasons for Declining

American Association of Clinical Declined, “endocrinologists are not Endocrinology Endocrinologists (AACE) generally in the compounding space.”

American Medical Association (AMA) Failed to respond Medicine American Osteopathic Association (AOA) Failed to respond

Neurology American Academy of Neurology (AAN) Failed to respond

Obstetrics and American College of Obstetricians and Declined, survey not approved for Gynecology Gynecologists (ACOG) distribution

American Academy of Family Physicians (AAFP) Failed to respond Primary Care American College of Physicians (ACP) Failed to respond

Declined, “our physicians are inundated Urology American Urology Association (AUA) with surveys and I’m afraid you won’t be able to get the information you need”

CURRENT AND HISTORIC USE Summary of background information • Estriol is not available as an FDA-approved product. • Estriol is not available as an OTC product in the US. • There is a current United States Pharmacopeia (USP) monograph for estriol. • Estriol is available in Australia, Belgium, New Zealand, and UK. In Abu Dhabi and Latvia, it is available in dosage forms other than the nominated forms.

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Table 3. Currently approved products – US No approved products in the US

Table 4. Currently approved products – select non-US countries and regionsa

Approved For Use Active Dosage Concentration ROA Ingredient Form Country Status Approval Dateb

Australia 9/20/1991 1mg/g Belgium 08/09/1983

Cream New Zealand 12/18/1986

Estriol 1mg Vaginal Prescription 08/20/1982 UK 0.01% 09/01/1995

Belgium 08/09/2016 50mcg/g Gel UK 12/08/2016 Abbreviations: “– “, not mentioned; ROA, route of administration. aMedicine registers of national regulatory agencies were searched if they met the following criteria: freely accessible; able to search and retrieve results in English language; and desired information (product trade name, active ingredient, strength, form, ROA, and approval status) provided in a useable format. Information was recorded only for products with strengths, forms and/or ROA similar to those requested in the nominations. See Methodology for full explanation. bIf multiple approval dates and/or multiple strengths, then earliest date provided.

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Summary of literature review • Total number of studies included: 297 studies (18 descriptive, 221 experimental, and 58 observational). • Most of the studies were from Italy (40). • The most common indication for the use of estriol in the US and non-US studies was post- menopause. • Compounded products were identified from both the US and non-US studies. One (1) US study utilized estriol in the nominated dosage form.

Table 5. Types of studies

Types of Studies Number of Studies

Descriptive1–18 18

Experimental19–239 221

Observational240–297 58

Table 6. Number of studies by countrya

Country Number of Studies

Argentina 20,207,217,219 4

Australia 2,120,243,284,293 5

Austria 44,49,92,93 4

Brazil13,55,82,98,178,184,208,209,230 9

Belgium7,33,34,60,77,137,146,191–193,213,289 12

Bulgaria 45 1

Canada68,69,235,251 4

China 61,171–173 4

Columbia104 1

Denmark81,111,144,176,177,185 6

Finland4,41,96,97,99,105,150,205,268,269,280 11

France180 1

Georgia 47 1

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Germany54,59,106,114,122,124,143,145,154,156,157,169,194,195,197,198,210,232,233,247,262,272,281,291 24

Greece254,255 2

Hungary30,282 2

India 12 1

Israel31,76,125,126,152 5

Italy48,64,65,70,74,91,109,115,116,139,140,158,159,161,162,164,165,167,168,170,183,188,201,214–216,220– 39 224,240,246,261,264,265,273,274,297

Japan6,36–38,56,57,79,127,128,135,148,151,239,242,244,257,258,286 18

New Zealand292 1

The Netherlands58,63,229,238,287 5

Norway21,32,51,52,199,295 6

Poland5,8,252 3

Portugal75 1

Romania271,277 2

Russia 42,196,207,218,228,249 6

Serbia 39 1

South Africa290 1

South Korea245 1

Spain16,80,89,108,160,181,182,187 8

Sweden3,18,22–29,35,43,50,71–73,78,83,87,107,131,163,174,179,202,203,241,253,256,260,283,285,296 33

Switzerland19,46,85,123 4

Taiwan149 1

Thailand40,67,134 3

Turkey86,138 2

Ukraine103 1

UK1,14,15,62,84,88,119,129,153,166,186,190,211,212,225,226,234,236,288 19

US9,11,17,66,100–102,110,112,113,117,118,121,132,133,136,141,142,147,155,175,189,200,204,227,231,237,248,250,263,275,276 32

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Yugoslavia90,130 2

Multiple Countries • Germany, Switzerland, Belgium 259 • Germany, Belgium266 4 • Italy, UK278 • UK, South Africa, Belgium267

Total US: 32 Total Non-US Countries: 258 aStudies 95, 270, 279 did not mention country.

Table 7. Number of studies by combinations No combination products were nominated

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Table 8. Dosage by indication – US

Indication Dose Concentration Dosage Form ROA Duration of Treatment

0.135-8mg/day Tablet Oral Once - 2 years – 0.5mg/day Cream 14-28 days Vaginal Postmenopause – symptoms not specified17,118,121,133,136,227,250,275 – 4mg/2ml Solution Once 6-100mg/day Intravenous – 0.25-0.5mg/day – Transdermal 3 years

4-8mg/day Tablet Oral Vasomotor mood symptoms (hot flash, night sweat9) in postmenopause263 – – – – Sublingual

1.5-3.5mg/week Cream 8 months Vaginal Postmenopausal urinary tract infection17,100–102 1-3.5mg/week – Pessary 9 months

1-56mg/week – – 14 days

1-8mg/day Tablet Oral 28 days

20-70mcg/week Cream 12 weeks Atrophic vaginitis237 in postmenopause9,11,17,118,132,175 1-3.5mg/week – Pessary Vaginal

2-7mg/week Suppository 6 months

2-56mg/week – – –

Aromatase inhibitor induced vaginal atrophy in breast cancer110 2-7g/week 0.005% Gel Vaginal 12 weeks

Prevention of mammary carcinoma in postmenopause248 5-15mg/day – – Oral 8-40 months

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Infertility9,189 0.25-8mg/day – Tablet Oral 30 days

Ovarian failure with amenorrhea237 1mg/day – – Oral 28 days

Vaginal maturation200 12mg/week – Cream Vaginal 6 weeks

2-56mg/week Tablet Oral

Pre/post-operative treatment in postmenopause9 2-7 applications/week – Cream Topical 4 weeks

1-3.5mg/week Pessary Vaginal

Vaginal treatment following sacral colpopexy204 2-7g/week – Cream Vaginal At least 2 weeks

Prevention of overactive bladder symptoms after tension-free vaginal tape 2-7mg/week – Ovule Intravaginal 6 months procedure155

Relapsing-remitting66,141 multiple sclerosis117 2-8mg/day – Capsule Oral 6-24 months

Prevention of postpartum multiple sclerosis relapse142 100mcg/week – Patch Transdermal 12 weeks

Skin aging17,112,276 1g/day 0.3% Cream Topical 6 months

Atrophic acne scars113 6mL/week 0.3% Solution Topical 3 months

Hereditary hemorrhagic telangiectasia-related epistaxis147,231 0.4mL/day 0.1% Spray Nasal 12 weeks

Reduce cardiovascular risk17 2mg/day – – – 3 months - 8 years

0.5mg every other day Vaginal – Osteoporosis prevention17 – – 2-12mg/day – 10 months - 2 years Abbreviations: “–“, not mentioned; ROA, route of administration.

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Table 9. Dosage by indication – non-US countries

Indication Dose Concentration Dosage Form ROA Duration of Treatment

1mg/day Solution Intravenous 12 hours - 10 days

1mg/day Capsule 1 year

1mg/day Suspension 6 weeks – Oral 0.27-12mg/day Tablet 5 days - 10 years

10mcg-12mg/day – 10 days - 48 months

0.5-7mg/week Cream 2 weeks - 6 years Postmenopause1,2,27,259,269,270,273,279,280,283,284,286,287,30,288,289,291–293,295– 297,35–38,41–43,45,3,53,56–60,62,65,67,68,16,69,73,74,76,78,80,81,87,96,98,18,99,103,109,111,122– 0.1-350mg/week 0.0005-0.005% Gel 3-15 weeks 125,127,128,21,131,135,139,145,146,149–151,158,159,23,160,161,163,164,166– 168,172,173,176,24,179,185–188,191,192,194,195,198,25,203,205,211– 60mcg-7mg/week Ovule 1 day - 6 months 215,217,225,226,26,230,232,234,236,239,244,246,251,252,256 1-3.5mg/week Pessary Vaginal 7-12 weeks

1-7mg/week – Suppository 1 months - 10 years

0.09-0.21mg/week Tablet 12 weeks

0.03-2mg/day – 4 weeks -12 months

– 0.1% Nanoemulsion Transdermal 60 months

0.5-6mg/day – – – 4 weeks - 6.4 year

0.09-28mg/week Tablet Oral 1 week - 24 months Vaginal atrophy4,10,48,64,71,72,77,89– 91,95,104,14,108,114,130,143,153,154,156,169,171,178,20,181,182,184,199,201,206,219,223,224,228,28, 1.5-3.5mg/week – Topical 12-20 weeks 229,233,238,245,249,255,261,262,265,266,29,271,294,33,34,40,46 Cream 0.25-10mg/week Vaginal 1-34 weeks

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100-350mg/week 0.002-0.005% Gel 8-15 weeks

0.5mg/day Ovule 8 weeks

0.06-1.4mg/week Pessary 21 days - 12 weeks

0.25-3.5mg/week Suppository 3-16 weeks – 0.03-0.21mg/week Tablet 12 days - 12 weeks

1-3.5mg/week 2 months - 10 years – 0.5-3.5mg/week – 6 weeks - 12 months

0.03mg/day Pessary 12 days

0.3mg/day Suppository Vaginal 6 days -6 weeks Bacterial vaginosis7,85,86,120,137,193,241 – 0.03mg/day 6-12 days Tablet 1-3mg/day Oral 12-19 weeks

2mg/day Tablet Oral 10-25 days

Dyspareunia82,115,183,264 1mg/day – Cream 10 days Topical 100mcg/week Gel 12 weeks

Vulvodynia216 – 12.5% Cream – 12 weeks

Amenorrhea129,220–222 2-12mg/day – Tablet Oral 10-90 days

1mg/day Cream/ointment Topical 4 weeks Labia synechia5,157,254 – – Gel Vaginal 6 months

Ovarian failure152,247 4mg/day – Tablet Oral 21-35 days

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Pre-procedure for hysterectomy242 1mg/day – Tablet Intravaginal 14 days

Neovagina creation243 – 0.1% Cream Intravaginal 2 weeks

Uterine leiomyomata79 4mg/day – Tablet Oral 4 months

80mg/month Solution Intramuscular 8 weeks

2-4mg/day Tablet Oral 1-3 months

0.5-7mg/week Topical 1-6 weeks Cream 1mg/day 2 weeks - 3 months Urinary – incontinence12,13,170,174,196,207,210,218,260,267,277,290,22,32,49,50,55,94,107,162 1.5mg/week Suppository 6 weeks Vaginal 2-7mg/week Ovule 24 weeks

0.5mg-3.5mg/week – 6 weeks

1-8mg/day – – 4 weeks - 3 months

1mg/2days Fluid Intravesical 3 weeks

1-3mg/day – Oral 10-16 weeks

Overactive bladder15,47,70,84,116,278 – – Cream 12-24 weeks

100-350mcg/week Gel Vaginal 15 weeks

3mg/day – 3 weeks

1-3mg/day Tablet Oral 11-12 weeks

Urinary tract infection1,51,52,93,274 1mg/day – Cream – Vaginal 2-7mg/week – 4 weeks

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– 0.005% Gel 15 weeks – 1mg/week – Pessary –

Aromatase inhibitor induced urogenital symptoms92 0.5mg/day – Tablet Vaginal 2 weeks

Contraceptive19 2mg/day – Tablet Oral 15 menstrual cycles

0.5mg/week-2mg/day Tablet Oral 21 days - 2 years

1-2mg/day Cream Osteoporosis1,39,61,63,177,197,253,257 – 2 years 0.5mg/12 weeks Ring Vaginal

0.5mg/day – –

Hyperlipidemia83,105,119,126,138,144,148,268 0.5-16mg/day – Tablet Oral 4 months - 6.4 years

Multiple sclerosis1,180,235,240 8mg/day – – Oral 6-10 months

2mg/day Tablet Oral 1 month Progressive systemic sclerosis6 – 10-20mg/week – Subcutaneous 9 months

0.03mg/day Globule Intravaginal 2 years Cancer1,8,31 – 1-2mg/day Tablet Oral During chemotherapy

Mammary fibroadenoma208,209 2mg/day – Capsule Oral 4 menstrual cycles

Epistaxis in hereditary hemorrhagic telangiectasia54,106,258,272 1mg/day 0.1% Ointment Intranasal 3-18 months

1-3.5mg/week Cream Vaginal 3 months Hormone replacement therapy-induced oral discomfort140,202 – 1mg/day Tablet – 1 year

Skin ageing44,97 0.1mg/day 0.3% Ointment Topical 3 weeks

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Plantar keratoderma climatericum75 0.125mg/day – Cream Topical 6 months

Gastric ulcer190 0.5mg/day – Tablet – –

Stroke prophylaxis285 1mg/day – – – –

Osler’s disease281 – 0.1% Ointment Nasal 2 years

Churg-Strauss syndrome282 1mg/day – – – 3 months Abbreviations: “–“, not mentioned; ROA, route of administration.

Table 10. Compounded products – US

Indication Publication Year Compounding Method Dosage Form Final Strength

• A compounded hormone cream was prepared by a compounding pharmacy using VersabaseTM, micronized progesterone USP (Professional Compounding Centers Postmenopause121,227 2008-2013 of America, Houston, Tex., USA), micronized estriol USP, micronized estradiol Cream 80% USP, micronized DHEA, micronized testosterone propionate USP (Hawkins Pharmaceutical Group, Minneapolis, Minn., USA)

Atrophic vaginitis in 2009 • Compounded with progesterone 30 mg Suppository – postmenopause175

HHT-related epitaxis231 2015 • In methylcellulose suspension Spray –

Vasomotor mood symptoms 2011 – – – in postmenopause263 Abbreviation: “–“, not mentioned.

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Table 11. Compounded products – non-US countries

Indication Compounding Method Dosage Form Final Strength

Menopause226 – Pessary –

Postmenopause61 • By the department of pharmaceutics at Xiangya Hospital China Tablet –

Inhibit the development of endometrial hyperplasia 179 – – –

Hereditary hemorrhagic telangiectasia258 – Ointment 0.1% Abbreviation: “–“, not mentioned.

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Summary of focus groups/interviews of medical experts and specialty organizations Four (4) interviews were conducted.

Table 12. Overview of interviewees

Level of Current Practice Experience Interviewee Specialty Interview Summary Response Training Setting with Estriol

Academic medical END_02 MD Endocrinology No • Does not see a need for use in office – can write a prescription for it to institution be compounded if really needed.

• Europe has approved an estriol product as a vaginal suppository, which works quite well for vaginal atrophy. US does not have any FDA-approved products. Obstetrics and Large midlife Not OBG_01 MD • In general, there is not a reason why you need to use estriol over gynecology health center specified estradiol. • Combination of estriol, estradiol, and estrone does not make sense from either an efficacy or safety standpoint.

• Estriol is not typically a one-off treatment as it is used more Not DER_06 MD Dermatology Consulting frequently. specified • No need in the office, can write prescription for it when needed.

• Does not stock estrogens in office • Would have concerns with stocking. Most practices are not set up to have it, and there is a concern of patients and staff taking this out Academic medical Not END_01 MD Endocrinology without permission. institution specified • Discourages use of estrogens. • Usually uses FDA-approved products. Exceptions may be due to cost. Abbreviation(s): MD, Doctor of Medicine.

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Efficacy/safety • One (1) interviewee stated that there was a myth that estriol prevents breast cancer, which was why some compounding pharmacies made combination products with estriol, but there is no evidence for this claim. The interviewee stated that estriol is just a weak estrogen, so if it is dosed high enough, there is the same risk for endometrial cancer and breast stimulation as with the use of other estrogens. Concerns with compounded hormone therapy • One (1) interviewee stated, “we held a phone call last October with the FDA as a group of societies [redacted] and met with multiple people from the FDA to raise some concerns about compounding hormone therapy, about the prevalence, about our concern about the limited group of people that should be receiving non-approved compounded hormone products. And our concerns about patient safety due to the lack of adequate regulatory oversight, lack of package inserts, and standard warnings. And then the false and misleading claims about bioidentical hormones.” • One (1) interviewee stated, “there's a lot of concern that we are giving post-menopausal women very high levels of hormones without any data showing safety or efficacy or need for those high doses.” Office use • Two (2) interviewees stated that there is no need for estriol in office since a prescription can be written for it to be compounded, if needed. Supplemental information: • One (1) interviewee provided references regarding the serious health and safety risks associated with the use of compounded “bioidentical” hormone products in menopausal women, as well as scientific, positional statements, and other publicly available documents nominating hormones to the demonstrably difficult to compound list.298-308 o Potency: estriol (E3) < estrone (E1) < estradiol (E2). In the presence of E2, E1 and E3 function as competitive inhibitors of E2 action, because they use the same receptor. Much of the custom-compounding literature interprets this to mean that E2, when administered alone, needs to be “balanced” with its natural antagonists, E1 and E3, in order to be truly physiologic. This logic forms the basis for compounds such as Biest (E2 plus E3 in a 20/80 formulation) and Triest (E1 plus E2 plus E3 in a 10/10/80 formulation). There is no medical evidence to support this notion.306

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Summary of survey results

Table 13. Characteristics of survey respondents [58 people responded to the surveya]

Board Certification DO MD ND No Response

Endocrinology, Diabetes and Metabolism 0 0 1 0

Fellow of the American Board of Naturopathic Oncology 0 0 1 0

Family Medicine 0 1 0 0

Integrative Medicine 0 1 0 0

Naturopathic Doctor 0 0 6 0

Naturopathic Physician 0 0 9 0

Obstetrics and gynecology 0 1 0 0

Rheumatology 1 0 0 0

No Board Certification 1 1 4 0

No Response 0 0 0 39 Abbreviations: DO, Doctor of Osteopathic Medicine; MD, Doctor of Medicine; ND, Naturopathic Doctor. aSome respondents reported more than one terminal clinical degree or board certification.

Table 14. Types of products used, prescribed, or recommended

Types of Products Respondents, n (N=41a)

Compounded 13b

FDA-approved 0

Over-the-counter 2

Dietary 1

Unsure 0

No Response 25 aOut of 58 respondents, 41 reported using, prescribing, or recommending estriol product. bTwelve (12) respondent used in combination. See Figure 2 below.

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Figure 2. Compounded combinations reported in the survey

Active ingredients in combination products: • Biest (Estriol / Estradiol) • Estriol / Progesterone • Estriol / Testosterone • Estriol / Estradiol / DHEA • Estriol / Estradiol / Progesterone • Estriol / Lactobacillus acidophilus and/or oxytocin • Estriol / Testosterone in Mucolox • Estriol / Estradiol / Progesterone / Testosterone • Estriol / Estradiol / Progesterone / Testosterone and/or DHEA • Estriol / DHEA / Hyaluronic acid / Testosterone / Vitamin A & E

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Table 15. Compounded use of estriol in practicea

Duration of Indication Strength Dosing frequency Dosage Form ROA Patient Population Treatment

Erosive desquamative 1-2mg Biweekly Suppository Intravaginal 3-6 months Older adult women vaginitis

Hormone balance, – – – – – – cancer protection

Hormone replacement Cream, tablet, Oral, sublingual, 0.5-12mg Daily Indefinitely Menopausal women (post breast cancer) troche, suppository topical, vaginal

Lichen sclerosus et 1-2mg BID “mg” Topical Indefinitely Peri/post-menopausal women atrophicus

0.7mg/g Daily 1 click – Topical Menopausal women 0.1-4mg Daily Indefinitely

1-2 years Peri/post-menopausal women 0.5-2mg Daily Transdermal Menopause symptoms 1-5 years Postmenopausal women (hot flashes, insomnia, Cream depression, 0.1-4mg/ml Nightly, daily As needed osteoporosis) Transdermal, Menopausal women vaginal 1-2mg Daily Ongoing

1.25mg Daily Vagina/labia 6 months – 2 years Women 45+

0.25mg/gtt Daily Tincture “sl” Long term Menopausal women

Premature ovarian 1.25mg Daily for 2 weeks Cream Vagina labia 3-6 months Women 20-35 failure

Recurrent urinary tract Every other day- Transdermal, 1-3mg Cream Long term Post menopause, post cancer infections, incontinence daily vaginal

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0.7mg/g Daily 1 click Topical – Menopausal

0.5-2mg Daily 1-5 years Transdermal 1-2mg Daily 1-3 years Postmenopausal women

0.5-2mg Daily Vaginal Indefinitely Cream Every other day- 1-3mg Long term Post menopause, post cancer daily Transdermal, vaginal Vaginal atrophy, 0.1-4mg/ml Nightly, daily As needed Menopausal women vulvovaginitis, vaginal dryness 5mg Biweekly Indefinitely Peri/post-menopausal women Suppository Daily for 2 weeks, 1mg Vaginal then 3x per week Ongoing Menopausal women

1-2mg Every other night Cream, suppository

0.1-3mg Daily-3x per week Cream, tablet Vaginal, skin Varies “Females > 50”

Cream, tablet, 0.5-8mg Nightly Topical, vaginal Indefinitely Menopausal women troche, suppository Abbreviations: “–“, not mentioned; ROA, route of administration; BID, twice daily. aTwelve (12) respondents. bQuotations are direct words from respondents.

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Table 16. Indications for which estriol is considered a standard therapy

Standard Therapy Indication Compounded, n (N=13) Non-compounded, n (N=3) No Response, n (N=25)

Cancer prevention 1 0 0

Hormone balance 2 0 0

Hormone replacement therapy 1 0 0

Lichen sclerosis et ateophicus 1 0 0

Menopause (osteoporosis, and other significant symptoms) 6 1 0

Painful intercourse 1 0 0

PMS 0 1 0

Premature ovarian failure 1 0 0

Vaginal atrophy/vaginal dryness with and without history of UTI 7 1 0

Vaginitis post menopause with high risk for breast cancer 1 0 0

Urinary incontinence 0 1 0

No response 1 0 25 Abbreviation: “–“, not mentioned. aSome respondents reported more than one indication.

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Table 17. Reasons for using compounded product instead of the FDA-approved products

Theme Reasons

• I don't think that horse estrogen is as safe or effective as human estrogen. The molecular structure is different and has more risks associated with it. Also, there are less dosing options and it is extremely expensive. Efficacy/ safety • Works better and does not stimulate the breast tissue or endometrial tissue • Better patient outcomes / use in patients post breast cancer • It is less inflammatory and also a less potent estrogen

Cost • Very expensive

• Not available and it is much more specific to pelvic tissues for the treatment of Availability vaginal atrophy than estradiol,

• I use low dose and ultra-low dose. Versatility • Versatility in dosing, route of administration. • Ability to titrate dose to patient need.

Patient preference • Usually, it is because patients do NOT want systemic absorption of estradiol.

Quality • FDA products contain potentially unsafe or irritating additives.

Table 18. Change in frequency of compounded estriol usage over the past 5 years

Respondents, n (N=13)

No–use has remained consistent 9

Yes–I use it LESS often now 0

Yes–I use it MORE often now • “Needed!” • “Seeing more menopausal women” 3 • “More comfortable with experience of use”

No Response 1

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Table 19. Do you stock non-patient specific compounded estriol in your practice?

Respondents, n (N=13)

No 11

Yesa 1

No Response 1 aRespondent reports stocking non-patient-specific compounded estriol in physician office, purchased from an outsourcing facility for convenience.

Table 20. Questions related to stocking non-patient specific compounded estriol No survey respondents provided this information

CONCLUSION Estriol (UNII code: FB33469R8E) was nominated for inclusion on the 503B Bulks List treatment of vaginal atrophy via a vaginal cream and gel. Estriol is not approved in the US, but is available in the nominated ROA and dosage form in Australia, Belgium, New Zealand, and UK. From the literature review conducted, the most common indication for the use of estriol in the US and non-US studies was post-menopause. Compounded products were identified from both the US and non- US studies. One (1) US study utilized estriol in the nominated dosage form. From the interviews, none of the four (4) interviewees expressed a need for compounded estriol to be stocked in the office. One (1) interviewee expressed concern about compounded hormone therapy. From the survey responses, 41 out of 58 respondents used estriol. The most common indications for use of compounded estriol were menopause and vaginal atrophy. Efficacy, safety, cost, availability, versatility, patient preference, and quality were some of the reasons for using the compounded estriol product over an FDA-approved product. Out of 13 respondents who used compounded estriol, one (1) respondent reported stocking compounded estriol in a physician office.

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301. Develen C. Comment from Carolyn Develen. Food and Drug Administration Notice: Drug Products That Present Demonstrable Difficulties for Compounding Under the Federal Food, Drug, and Cosmetic Act. 2018. https://www.regulations.gov/document?D=FDA-2017-N-2562- 0017. Published October 9, 2018. Accessed November 27, 2019. 302. Endocrine Society. Comment from Endocrine Society. Food and Drug Administration Notice: Drug Products That Present Demonstrable Difficulties for Compounding Under the Federal Food, Drug, and Cosmetic Act. 2017. https://www.regulations.gov/document?D=FDA-2017-N-2562- 0006. Published December 14, 2017. Accessed November 22, 2019. 303. Endocrine Society. Compounded bioidentical hormone therapy. An Endocrine Society Position Statement. 2019. https://www.endocrine.org/news-and-advocacy/position- statements/compounded-bioidentical-hormone-therapy. Published October 2, 2019. Accessed November 27, 2019. 304. Pinkerton J, Sánchez Aguirre F, Blake J, et al. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728-753. 305. Pinkerton JV, Conner EA, Kaunitz AM. Management of menopause and the role For hormone therapy. Clin Obstet Gynecol. 2019;62(4):677-686. 306. Santoro N, Braunstein GD, Butts CL, Martin KA, McDermott M, Pinkerton JV. Compounded bioidentical hormones in endocrinology practice: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2016;101(4):1318-1343. 307. Stamoran C. Comment from Catalent Applied Drug Delivery Institute. Food and Drug Administration Notice: Drug Products That Present Demonstrable Difficulties for Compounding Under the Federal Food, Drug, and Cosmetic Act. 2018. https://www.regulations.gov/document?D=FDA-2017-N-2562-0011. Published May 7, 2018. Accessed November 27, 2019. 308. Utian W. Comment from Wulf Utian. Food and Drug Administration (FDA) Proposed Rule: Drug Products That Present Demonstrable Difficulties for Compounding Under Sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act. 2014. https://www.regulations.gov/document?D=FDA-2013-N-1523-0036. Published July 8, 2014. Accessed November 22, 2019.

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Appendix 2. Survey instrument Start of Block: Welcome Page The University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), in collaboration with the Food and Drug Administration (FDA), is conducting research regarding the use of certain bulk drug substances nominated for use in compounding by outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act. In particular, we are interested in the current and historic use of these substances in clinical practice. This survey is for estriol. As a medical expert, we appreciate your input regarding the use of this substance in your clinical practice. This information will assist FDA in its development of a list of bulk drug substances that outsourcing facilities can use in compounding under section 503B of the Act. All responses are anonymous. OMB Control No. 0910-0871 Expiration date: June 30, 2022 The time required to complete this information collection is estimated to average 30 minutes, including the time to review instructions, search existing data sources, gather the data needed, and complete and review the information collection. An agency may not conduct or sponsor, and a person is not required to respond to a collection of information unless it displays a currently valid OMB control number. If you have additional questions or concerns about this research study, please email: [email protected]. If you have questions about your rights as a research subject, please contact HRPO at 410-760-5037 or [email protected]. End of Block: Welcome Page

Start of Block: Estriol Q1. What type(s) of product(s) do you use, prescribe, or recommend for estriol? Please check all that apply. ▢ Compounded drug product ▢ FDA-approved drug product ▢ Over the counter drug product ▢ Dietary supplement (e.g. vitamin or herbal supplement products sold in retail setting) ▢ Unsure Skip To: Q13 If What type(s) of product(s) do you use, prescribe, or recommend for estriol? Please check all th... != Compounded drug product Skip To: Q2 If What type(s) of product(s) do you use, prescribe, or recommend for estriol? Please check all th... = Compounded drug product

Display This Question: If What type(s) of product(s) do you use, prescribe, or recommend for estriol? Please check all th... = Compounded drug product

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Q2. Please list any conditions or diseases for which you use compounded estriol in your practice. Please include the strength(s), dosing frequency(ies), dosage form(s), route(s) of administration, duration of therapy, and patient population (ex. age, gender, comorbidities, allergies, etc).

Strength(s) Dosing Dosage Route(s) of Duration of Patient (please frequency(ies) form(s) administration therapy population include units)

Condition 1 (please describe)

Condition 2 (please describe)

Condition 3 (please describe)

Condition 4 (please describe)

Condition 5 (please describe)

Q3. Do you use compounded estriol as a single agent active ingredient, or as one active ingredient in a combination product? Please check all that apply. ▢ Single ▢ Combination Skip To: Q5 If Do you use compounded estriol as a single agent active ingredient, or as one active ingredient... != Combination Display This Question: If Loop current: Do you use compounded estriol as a single agent active ingredient, or as one active ingredient... = Combination Q4. Please list all combination products in which you use compounded estriol.

______Q5. For which, if any, diseases or conditions do you consider compounded estriol standard therapy? ______Q6. Does your specialty describe the use of compounded estriol in medical practice guidelines or other resources? ______Q7. Over the past 5 years, has the frequency in which you have used compounded estriol changed? o Yes - I use it MORE often now (briefly describe why) ______o Yes - I use it LESS often now (briefly describe why) ______o No - use has remained consistent

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Q8. Why do you use compounded estriol instead of any FDA-approved drug product? ______Q9. Do you stock non-patient-specific compounded estriol in your practice location? o Yes o No Skip To: End of Block If Do you stock non-patient-specific compounded estriol in your practice location? = No Display This Question: If Do you stock non-patient-specific compounded estriol in your practice location? = Yes Q10. In what practice location(s) do you stock non-patient-specific compounded estriol? Please check all that apply. ▢ Physician office ▢ Outpatient clinic ▢ Emergency room ▢ Operating room ▢ Inpatient ward ▢ Other (please describe) ______Q11. How do you obtain your stock of non-patient-specific compounded estriol? Please check all that apply. ▢ Purchase from a compounding pharmacy ▢ Purchase from an outsourcing facility ▢ Compound the product yourself ▢ Other (please describe) ______Q12. Why do you keep a stock of non-patient-specific compounded estriol? Please check all that apply. ▢ Convenience ▢ Emergencies ▢ Other (please describe) ______Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded estriol? Please check all that apply. = Convenience Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded estriol? Please check all that apply. = Emergencies Skip To: End of Block If Why do you keep a stock of non-patient-specific compounded estriol? Please check all that apply. = Other (please describe) Q13. For which, if any, diseases or conditions do you consider estriol standard therapy? ______Q14. Does your specialty describe the use of estriol in medical practice guidelines or other resources? ______End of Block: Estriol

Start of Block: Background Information

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Q15. What is your terminal clinical degree? Please check all that apply. ▢ Doctor of Medicine (MD) ▢ Doctor of Osteopathic Medicine (DO) ▢ Doctor of Medicine in Dentistry (DMD/DDS) ▢ Naturopathic Doctor (ND) ▢ Nurse Practitioner (NP) ▢ Physician Assistant (PA) ▢ Other (please describe) ______Q16. Which of the following Board certification(s) do you hold? Please check all that apply. ▢ No Board certification ▢ Allergy and Immunology ▢ Anesthesiology ▢ Cardiovascular Disease ▢ Critical Care Medicine ▢ Dermatology ▢ Emergency Medicine ▢ Endocrinology, Diabetes and Metabolism ▢ Family Medicine ▢ Gastroenterology ▢ Hematology ▢ Infectious Disease ▢ Internal Medicine ▢ Medical Toxicology ▢ Naturopathic Doctor ▢ Naturopathic Physician ▢ Nephrology ▢ Neurology ▢ Obstetrics and Gynecology ▢ Oncology ▢ Ophthalmology ▢ Otolaryngology ▢ Pain Medicine ▢ Pediatrics ▢ Psychiatry ▢ Rheumatology ▢ Sleep Medicine ▢ Surgery (please describe) ______▢ Urology ▢ Other (please describe) ______End of Block: Background Information

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