9/13/2018 REVIEW VAGINAL ESTROGEN SAFETY AND • Timeline LABELING: STATE OF THE SCIENCE • Class labeling Carolyn J. Crandall, MD, MS, FACP, NCMP Professor of Medicine • Safety data David Geffen School of Medicine at the University of California, Los Angeles REVIEW Vaginal estrogen cream • Timeline initial approval 1946 (conjugated equine • Class labeling estrogens) then 1984 (E 2 ) • Safety data 1946 cream 1
9/13/2018 Vaginal estradiol tablets Vaginal estradiol rings (inserts) initial initial approval 1996 approval 2009 1946 1996 2009 1946 1996 cream ring insert (tablet) cream ring VAGINAL DEHYDROEPIANDROSTERONE (DHEA) NOT OUR FOCUS TODAY Vaginal insert FDA-approved 2016 Estradiol dose is 6X higher than Estring (which is 7.5 micrograms/day) Estrogen is a metabolite of prasterone, so I include it today. 1946 1996 2009 2016 cream ring insert (tablet) dehydroepiandrosterone 2
9/13/2018 REVIEW FIRST, THE FOREST VIEW • Timeline • Class labeling • Safety data Vincent van Gogh, Trees and Undergrowth , 1887 SO….WHAT DO WE KNOW ABOUT CLASS LABELING SAFETY FROM VAGINAL TRIALS? • Low-dose vaginal estrogen preparations approved by the U.S. Food and Drug Administration carry the same boxed warning about health risks as the systemic formulations of estrogen alone and combination estrogen plus progestogen carry. • This labeling is based on extrapolations of data from clinical trials of systemic hormone therapy, which: • involved substantially higher levels of systemic exposure, and • were not based on evidence from clinical trials of vaginal estrogen. (https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs- gen/documents/document/ucm075090.pdf FDA guidance) 3
9/13/2018 WHAT’S THE LEVEL OF EVIDENCE REVIEW BEHIND THE LABELING? • Timeline • Class labeling • Safety data Van Gogh, Undergrowth with Two Figures, 1890 EVIDENCE BEHIND THE LABEL: NOW THE SAME EXERCISE FOR PRASTERONE VAGINAL ESTRADIOL TABLETS • WARNINGS AND PRECAUTIONS Based on: “Estrogen is a metabolite of • … 17 steps long! prasterone. Prasterone has not been studied in women with a h/o breast cancer. Use of exogenous estrogen is contraindicated in women with a suspected history of breast cancer.” • Current or Past History of Breast Cancer. • ADVERSE REACTIONS • In four 12-week placebo-controlled RCTs, the most common adverse reaction with an incidence ≥ 2% was vaginal discharge. • In one 52-week open-label clinical trial, the most common adverse reactions with an incidence ≥ 2 percent were vaginal discharge and abnormal Pap smear. www.fda.gov 4
9/13/2018 EVIDENCE BEHIND THE LABEL: EVIDENCE BEHIND THE LABEL: VAGINAL ESTRADIOL TABLET VAGINAL ESTRADIOL TABLET Warnings: Warnings: 1. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. 2. In the Women’s Health Initiative estrogen -alone study, there was a. increased risk of stroke and DVT. b. Increased risk of probable dementia in postmenopausal women 65 years of age and older 3. The WHI estrogen plus progestin substudy found increased risks of: a. stroke, DVT, PE, MI, and breast cancer b. Probable dementia in women 65 years of age and older EVIDENCE BEHIND THE LABEL: EVIDENCE BEHIND THE LABEL: VAGINAL ESTRADIOL TABLET VAGINAL ESTRADIOL TABLET Warnings: BASED ON TRIALS OF ESTROGEN PILLS. DO VAGINAL Contraindications ESTROGENS CAUSE SAME SERIOUS AES? NO CLINICAL TRIAL DATA EXIST. 1. Undiagnosed abnormal genital bleeding 1. There is an increased risk of endometrial cancer in a woman with a 2. History of breast cancer (or suspected) uterus who uses unopposed estrogens. 3. Known or suspected estrogen-dependent neoplasia 2. In the Women’s Health Initiative estrogen -alone study, there was 4. History of DVT or PE, a. increased risk of stroke and DVT. 5. History of arterial thromboembolic disease, such as stroke or MI b. Increased risk of probable dementia in postmenopausal women 65 years of age and older 6. Liver impairment or disease 3. The WHI estrogen plus progestin substudy found increased risks of: 7. Known protein C, protein S, or antithrombin deficiency, other a. stroke, DVT, PE, MI, and breast cancer thrombophilic disorders b. Probable dementia in women 65 years of age and older 8. Known or suspected pregnancy 5
9/13/2018 EVIDENCE BEHIND THE LABEL: EVIDENCE BEHIND THE LABEL: VAGINAL ESTRADIOL TABLET VAGINAL ESTRADIOL TABLET Contraindications DITTO. NO DATA FROM VAGINAL ESTROGEN RCTS • Warnings and precautions 1. Undiagnosed abnormal genital bleeding 1. Estrogens increase the risk of gallbladder disease 2. History of breast cancer (or suspected) 2. We have to monitor thyroid function if you are taking thyroid 3. Known or suspected estrogen-dependent neoplasia replacement therapy 4. History of DVT or PE, 3. We need to check whether you are taking drugs that affect 5. History of arterial thromboembolic disease, such as stroke or MI estrogen drug metabolism (inducers and inhibitors of CYP3A4). 6. Liver impairment or disease 7. Known protein C, protein S, or antithrombin deficiency, other thrombophilic disorders 8. Known or suspected pregnancy EVIDENCE BEHIND THE LABEL: EVIDENCE BEHIND THE LABEL: VAGINAL ESTRADIOL TABLET VAGINAL ESTRADIOL TABLET • Warnings and precautions THESE POINTS ARE FROM ORAL, NOT • The only adverse events information on the label that isn’t based on VAGINAL, ESTROGEN STUDIES WHI is: 1. Estrogens increase the risk of gallbladder disease • One pcRCT each for vaginal estradiol 10 mcg tablets (12-mo) and 2. We have to monitor thyroid function if you are taking thyroid 25 mcg tablets (12-week) replacement therapy 3. We need to check whether you are taking drugs that affect estrogen drug metabolism (inducers and inhibitors of CYP3A4). In fact, it says “no drug -drug interaction studies have been performed for Vagifem ”! 6
9/13/2018 BY THE WAY • Because of class labeling, the same warnings, precautions, contraindications, drug interaction information is listed for: • Premarin vaginal CEE cream • Estring vaginal estradiol ring • Estradiol cream SO WHAT DO WE KNOW ABOUT VAGINAL ESTROGEN SAFETY FROM VAGINAL ESTROGEN TRIALS? • Endometrial safety • Serum levels 7
9/13/2018 Cochrane systematic review 2016 SO WHAT DO WE KNOW ABOUT 4 studies of endometrial thickness included VAGINAL ESTROGEN SAFETY FROM Cream vs. ring Cream vs. tablet VAGINAL ESTROGEN TRIALS? • Endometrial safety • GSM symptoms can’t be expected to resolve on their own. We expect them to persist or worsen, so long-term endometrial safety data are of great interest. • Serum levels (Lethaby et al Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD001500) Cochrane systematic review 2016 BUT .… 4 studies of endometrial thickness included Cream vs. ring Cream vs. tablet -CEE cream may be associated with ↑ -No difference in endometrial in endometrial thickness vs E 2 ring (OR thickness between vaginal E 2 • The 2016 Cochrane Systematic Review: 0.36, 95% CI 0.14-0.94 ring vs. crm) tablet and CEE cream 2X/wk • Found that the longest intervention duration re endo thickness was only 6 months! (Rioux et al Menopause 2000) -This may be due to the higher doses (Manonai 2001 E 2 tablet • Did not evaluate endometrial biopsy (EMB), hyperplasia, or cancer of cream (Ayton Br J Obstet Gynaecol. 25mcg once/wk or CEE 1996 used 0.625mg CEE nightly 3 wks cream 1gm = 0.625mg 2X/wk on and 1 wk off vs. estradiol ring 5-10 X 10 wks; Rioux 2000 E 2 tablet • So, what are data from systematic EMB studies? mcg/d; Nachtigall Maturitas 1995 used 25mcg once/wk or CEE 2g = 1.25mg CEE 3X/wk vs. E 2 ring 10mcg/d; 1.25mg/d X 21 days f/b 1 wk both 12-wk intervention) off for 6-month intervention). (Lethaby et al Cochrane -Thickness of >5 mm in 12% cream vs. Database of Systematic Reviews 6% ring users. (Nachtigall 1995) 2016, Issue 8. Art. No.: CD001500) 8
9/13/2018 LONGEST SYSTEMATIC EMB DATA LONGEST SYSTEMATIC EMB DATA • tablet vs. crm – 6 months • Prasterone: • estradiol tablet 25mcg once/wk or CEE cream 1.25 mg/d X 21 • E2 made in peripheral tissues from DHEA exerts action locally in days f/b 1 wk off for 6-month intervention the same cells where synthesis takes place with only minimal release into the circulation. (Labrie et al Menopause 2009) • tablet: 1/49 proliferative endometrium; • Enzymes transform DHEA into estrogens are absent in the • cream: 7/49 proliferative endometrium, 2/49 endometrial endometrium (Portman et al Menopause 2015) hyperplasia) (Rioux et al Menopause 2000) • Endometrial atrophy or inactive endometrium in all women • Tablet without comparison group-12 months (Portman et al Menopause 2015, 52 wk; Archer et al Menopause • estradiol vaginal tablet 10mcg, 2 studies 2015, 12 wk) • no hyperplasia or endometrial ca (Ulruch Climacteric 2010) • 2 events of hyperplasia and carcinoma in 386 evaluable biopsy samples (incidence rate 0.52% per year)(vs. background incidence of 0%-1%)(Simon Obstet Gynecol 2010) SO WHAT DO WE KNOW ABOUT VAGINAL ESTROGEN SAFETY FROM SERUM LEVELS HEAD-TO-HEAD VAGINAL ESTROGEN TRIALS? Vaginal • Endometrial safety estradiol tablet vs. placebo Vaginal Vaginal • Serum levels — surrogate for systemic effects, particularly during estradiol tablet maintenance phase estradiol tablet vs. ring vs. CEE cream (won’t discuss studies without a comparison group) 9
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