Graham S, Constantine G, Margulis AV, Saltus CW, Johannes CB, Kaye JA, Mirkin S. A postmarketing noninterventional study evaluating the risk of endometrial cancer in women who have been prescribed Imvexxy® - study design. Poster presented at the 2021 North American Menopause Society (NAMS) Annual Meeting; September 22, 2021. [abstract] Menopause. 2021; 28(12):1462(P28). doi: 10.1097/GME.0000000000001890

BACKGROUND: Prescribing information for all estrogen products, regardless of route of administration, state that “Generally, when estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be considered to reduce the risk of endometrial cancer.” However, a comprehensive literature review evaluating low-dose vaginal estrogens (LDVE) did not support an increased risk of endometrial hyperplasia or cancer (EC)1. Studies to date have been of relatively short duration and may have been underpowered for the detection of potential EC. Longer-term studies are evaluating the endometrial safety profile of LDVE.

OBJECTIVES: The objectives of this study are to: (1) estimate the risk of EC in women who have been prescribed Imvexxy (a very-LDVE, defined as ≤ 10 µg estradiol as the recommended daily dose [RDD]), (2) describe the duration and patterns of use of Imvexxy and other vaginal estrogen products, and (3) to estimate the risk of EC in women who have been prescribed any very-LDVE product (defined as ≤ 10 µg estradiol or ≤ 0.3 conjugated estrogens as RDD, including Imvexxy).

METHODS: This cohort study will be conducted using existing insurance claims data sources in the US. A feasibility assessment explored the capability of several data sources to validate EC cases and identify the data elements that are critical to this study. Two data sources were selected. Yearly monitoring reports will provide counts of Imvexxy-exposed patients and person-time in the data sources. A validation study with medical record review will be implemented to validate an electronic algorithm to identify EC (using ICD-10-CM codes), which will be used in the safety study. The final report will include results of the drug utilization study (Objective 2) and safety study (Objectives 1 and 3). Inclusion and exclusion criteria are shown below. Each exclusion criterion will be assessed using all available information in each data source before the start of observation in the safety study. Inclusion Criteria • age 50 years or older • continuous enrollment of at least 12 months in a health plan with complete medical and pharmacy benefits • routine visits to a gynecologist or to a primary care physician for gynecological exams Exclusion Criteria • documented hysterectomy (partial or total) • history of endometrial cancer, endometrial hyperplasia, or endometrial ablation (to ensure that any case of endometrial cancer is an incident case) • prior use of any vaginal estrogen product Additional Exclusion Criteria for Objective 1 • history of estrogen-dependent cancers listed in Imvexxy’s label (breast or ovarian cancer) The study outcome is defined clinically as the first EC after cohort entry and will be ascertained using the previously validated algorithm. Exposure will be identified in electronic data based on dispensed prescriptions for Imvexxy 4 μg or 10 μg (Objective 1) or any very-LDVE product (Objective 3). Variables to describe the study population and variables that may confound the association between the use of very-LDVE and EC will be collected. Safety analyses will compare users of Imvexxy (Objective 1) or of any very-LDVE (Objective 3) with comparable women who do not use vaginal estrogen products using regression models. Confounding control will be implemented through propensity-score matching. The target study size, based on background rates of EC in postmenopausal women, for the analyses for very-LDVE, to exclude a hazard ratio of 2, is 109,200 person-years (36,400 exposed person-years and 72,800 unexposed person-years with a 1:2 ratio of exposed to unexposed, or, equivalently, a total of 81 EC cases).

RESULTS: Monitoring counts will be produced yearly, starting in December 2021. The EC validation study is projected to be completed in 2022 and the safety study will be completed in 2025.

CONCLUSION: Results from this large observational study of the use of very-LDVE will provide additional information on the long-term endometrial safety of LDVE products.

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